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1. GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Author

Stevelink, R, Campbell, C, Chen, S, Abou-Khalil, B, Adesoji, OM, Afawi, Z, Amadori, E, Anderson, A, Anderson, J, Andrade, DM, Annesi, G, Auce, P, Avbersek, A, Bahlo, M, Baker, MD, Balagura, G, Balestrini, S, Barba, C, Barboza, K, Bartolomei, F, Bast, T, Baum, L, Baumgartner, T, Baykan, B, Bebek, N, Becker, AJ, Becker, F, Bennett, CA, Berghuis, B, Berkovic, SF, Beydoun, A, Bianchini, C, Bisulli, F, Blatt, I, Bobbili, DR, Borggraefe, I, Bosselmann, C, Braatz, V, Bradfield, JP, Brockmann, K, Brody, LC, Buono, RJ, Busch, RM, Caglayan, H, Campbell, E, Canafoglia, L, Canavati, C, Cascino, GD, Castellotti, B, Catarino, CB, Cavalleri, GL, Cerrato, F, Chassoux, F, Cherny, SS, Cheung, C-L, Chinthapalli, K, Chou, I-J, Chung, S-K, Churchhouse, C, Clark, PO, Cole, AJ, Compston, A, Coppola, A, Cosico, M, Cossette, P, Craig, JJ, Cusick, C, Daly, MJ, Davis, LK, de Haan, G-J, Delanty, N, Depondt, C, Derambure, P, Devinsky, O, Di Vito, L, Dlugos, DJ, Doccini, V, Doherty, CP, El-Naggar, H, Elger, CE, Ellis, CA, Eriksson, JG, Faucon, A, Feng, Y-CA, Ferguson, L, Ferraro, TN, Ferri, L, Feucht, M, Fitzgerald, M, Fonferko-Shadrach, B, Fortunato, F, Franceschetti, S, Franke, A, French, JA, Freri, E, Gagliardi, M, Gambardella, A, Geller, EB, Giangregorio, T, Gjerstad, L, Glauser, T, Goldberg, E, Goldman, A, Granata, T, Greenberg, DA, Guerrini, R, Gupta, N, Haas, KF, Hakonarson, H, Hallmann, K, Hassanin, E, Hegde, M, Heinzen, EL, Helbig, I, Hengsbach, C, Heyne, HO, Hirose, S, Hirsch, E, Hjalgrim, H, Howrigan, DP, Hucks, D, Hung, P-C, Iacomino, M, Imbach, LL, Inoue, Y, Ishii, A, Jamnadas-Khoda, J, Jehi, L, Johnson, MR, Kalviainen, R, Kamatani, Y, Kanaan, M, Kanai, M, Kantanen, A-M, Kara, B, Kariuki, SM, Kasperaviciute, D, Trenite, DK-N, Kato, M, Kegele, J, Kesim, Y, Khoueiry-Zgheib, N, King, C, Kirsch, HE, Klein, KM, Kluger, G, Knake, S, Knowlton, RC, Koeleman, BPC, Korczyn, AD, Koupparis, A, Kousiappa, I, Krause, R, Krenn, M, Krestel, H, Krey, I, Kunz, WS, Kurki, MI, Kurlemann, G, Kuzniecky, R, Kwan, P, Labate, A, Lacey, A, Lal, D, Landoulsi, Z, Lau, Y-L, Lauxmann, S, Leech, SL, Lehesjoki, A-E, Lemke, JR, Lerche, H, Lesca, G, Leu, C, Lewin, N, Lewis-Smith, D, Li, GH-Y, Li, QS, Licchetta, L, Lin, K-L, Lindhout, D, Linnankivi, T, Lopes-Cendes, I, Lowenstein, DH, Lui, CHT, Madia, F, Magnusson, S, Marson, AG, May, P, McGraw, CM, Mei, D, Mills, JL, Minardi, R, Mirza, N, Moller, RS, Molloy, AM, Montomoli, M, Mostacci, B, Muccioli, L, Muhle, H, Mueller-Schlueter, K, Najm, IM, Nasreddine, W, Neale, BM, Neubauer, B, Newton, CRJC, Noethen, MM, Nothnagel, M, Nuernberg, P, O'Brien, TJ, Okada, Y, Olafsson, E, Oliver, KL, Ozkara, C, Palotie, A, Pangilinan, F, Papacostas, SS, Parrini, E, Pato, CN, Pato, MT, Pendziwiat, M, Petrovski, S, Pickrell, WO, Pinsky, R, Pippucci, T, Poduri, A, Pondrelli, F, Powell, RHW, Privitera, M, Rademacher, A, Radtke, R, Ragona, F, Rau, S, Rees, MI, Regan, BM, Reif, PS, Rhelms, S, Riva, A, Rosenow, F, Ryvlin, P, Saarela, A, Sadleir, LG, Sander, JW, Sander, T, Scala, M, Scattergood, T, Schachter, SC, Schankin, CJ, Scheffer, IE, Schmitz, B, Schoch, S, Schubert-Bast, S, Schulze-Bonhage, A, Scudieri, P, Sham, P, Sheidley, BR, Shih, JJ, Sills, GJ, Sisodiya, SM, Smith, MC, Smith, PE, Sonsma, ACM, Speed, D, Sperling, MR, Stefansson, H, Stefansson, K, Steinhoff, BJ, Stephani, U, Stewart, WC, Stipa, C, Striano, P, Stroink, H, Strzelczyk, A, Surges, R, Suzuki, T, Tan, KM, Taneja, RS, Tanteles, GA, Tauboll, E, Thio, LL, Thomas, GN, Thomas, RH, Timonen, O, Tinuper, P, Todaro, M, Topaloglu, P, Tozzi, R, Tsai, M-H, Tumiene, B, Turkdogan, D, Unnsteinsdottir, U, Utkus, A, Vaidiswaran, P, Valton, L, van Baalen, A, Vetro, A, Vining, EPG, Visscher, F, von Brauchitsch, S, von Wrede, R, Wagner, RG, Weber, YG, Weckhuysen, S, Weisenberg, J, Weller, M, Widdess-Walsh, P, Wolff, M, Wolking, S, Wu, D, Yamakawa, K, Yang, W, Yapici, Z, Yucesan, E, Zagaglia, S, Zahnert, F, Zara, F, Zhou, W, Zimprich, F, Zsurka, G, Ali, QZ, Stevelink, R, Campbell, C, Chen, S, Abou-Khalil, B, Adesoji, OM, Afawi, Z, Amadori, E, Anderson, A, Anderson, J, Andrade, DM, Annesi, G, Auce, P, Avbersek, A, Bahlo, M, Baker, MD, Balagura, G, Balestrini, S, Barba, C, Barboza, K, Bartolomei, F, Bast, T, Baum, L, Baumgartner, T, Baykan, B, Bebek, N, Becker, AJ, Becker, F, Bennett, CA, Berghuis, B, Berkovic, SF, Beydoun, A, Bianchini, C, Bisulli, F, Blatt, I, Bobbili, DR, Borggraefe, I, Bosselmann, C, Braatz, V, Bradfield, JP, Brockmann, K, Brody, LC, Buono, RJ, Busch, RM, Caglayan, H, Campbell, E, Canafoglia, L, Canavati, C, Cascino, GD, Castellotti, B, Catarino, CB, Cavalleri, GL, Cerrato, F, Chassoux, F, Cherny, SS, Cheung, C-L, Chinthapalli, K, Chou, I-J, Chung, S-K, Churchhouse, C, Clark, PO, Cole, AJ, Compston, A, Coppola, A, Cosico, M, Cossette, P, Craig, JJ, Cusick, C, Daly, MJ, Davis, LK, de Haan, G-J, Delanty, N, Depondt, C, Derambure, P, Devinsky, O, Di Vito, L, Dlugos, DJ, Doccini, V, Doherty, CP, El-Naggar, H, Elger, CE, Ellis, CA, Eriksson, JG, Faucon, A, Feng, Y-CA, Ferguson, L, Ferraro, TN, Ferri, L, Feucht, M, Fitzgerald, M, Fonferko-Shadrach, B, Fortunato, F, Franceschetti, S, Franke, A, French, JA, Freri, E, Gagliardi, M, Gambardella, A, Geller, EB, Giangregorio, T, Gjerstad, L, Glauser, T, Goldberg, E, Goldman, A, Granata, T, Greenberg, DA, Guerrini, R, Gupta, N, Haas, KF, Hakonarson, H, Hallmann, K, Hassanin, E, Hegde, M, Heinzen, EL, Helbig, I, Hengsbach, C, Heyne, HO, Hirose, S, Hirsch, E, Hjalgrim, H, Howrigan, DP, Hucks, D, Hung, P-C, Iacomino, M, Imbach, LL, Inoue, Y, Ishii, A, Jamnadas-Khoda, J, Jehi, L, Johnson, MR, Kalviainen, R, Kamatani, Y, Kanaan, M, Kanai, M, Kantanen, A-M, Kara, B, Kariuki, SM, Kasperaviciute, D, Trenite, DK-N, Kato, M, Kegele, J, Kesim, Y, Khoueiry-Zgheib, N, King, C, Kirsch, HE, Klein, KM, Kluger, G, Knake, S, Knowlton, RC, Koeleman, BPC, Korczyn, AD, Koupparis, A, Kousiappa, I, Krause, R, Krenn, M, Krestel, H, Krey, I, Kunz, WS, Kurki, MI, Kurlemann, G, Kuzniecky, R, Kwan, P, Labate, A, Lacey, A, Lal, D, Landoulsi, Z, Lau, Y-L, Lauxmann, S, Leech, SL, Lehesjoki, A-E, Lemke, JR, Lerche, H, Lesca, G, Leu, C, Lewin, N, Lewis-Smith, D, Li, GH-Y, Li, QS, Licchetta, L, Lin, K-L, Lindhout, D, Linnankivi, T, Lopes-Cendes, I, Lowenstein, DH, Lui, CHT, Madia, F, Magnusson, S, Marson, AG, May, P, McGraw, CM, Mei, D, Mills, JL, Minardi, R, Mirza, N, Moller, RS, Molloy, AM, Montomoli, M, Mostacci, B, Muccioli, L, Muhle, H, Mueller-Schlueter, K, Najm, IM, Nasreddine, W, Neale, BM, Neubauer, B, Newton, CRJC, Noethen, MM, Nothnagel, M, Nuernberg, P, O'Brien, TJ, Okada, Y, Olafsson, E, Oliver, KL, Ozkara, C, Palotie, A, Pangilinan, F, Papacostas, SS, Parrini, E, Pato, CN, Pato, MT, Pendziwiat, M, Petrovski, S, Pickrell, WO, Pinsky, R, Pippucci, T, Poduri, A, Pondrelli, F, Powell, RHW, Privitera, M, Rademacher, A, Radtke, R, Ragona, F, Rau, S, Rees, MI, Regan, BM, Reif, PS, Rhelms, S, Riva, A, Rosenow, F, Ryvlin, P, Saarela, A, Sadleir, LG, Sander, JW, Sander, T, Scala, M, Scattergood, T, Schachter, SC, Schankin, CJ, Scheffer, IE, Schmitz, B, Schoch, S, Schubert-Bast, S, Schulze-Bonhage, A, Scudieri, P, Sham, P, Sheidley, BR, Shih, JJ, Sills, GJ, Sisodiya, SM, Smith, MC, Smith, PE, Sonsma, ACM, Speed, D, Sperling, MR, Stefansson, H, Stefansson, K, Steinhoff, BJ, Stephani, U, Stewart, WC, Stipa, C, Striano, P, Stroink, H, Strzelczyk, A, Surges, R, Suzuki, T, Tan, KM, Taneja, RS, Tanteles, GA, Tauboll, E, Thio, LL, Thomas, GN, Thomas, RH, Timonen, O, Tinuper, P, Todaro, M, Topaloglu, P, Tozzi, R, Tsai, M-H, Tumiene, B, Turkdogan, D, Unnsteinsdottir, U, Utkus, A, Vaidiswaran, P, Valton, L, van Baalen, A, Vetro, A, Vining, EPG, Visscher, F, von Brauchitsch, S, von Wrede, R, Wagner, RG, Weber, YG, Weckhuysen, S, Weisenberg, J, Weller, M, Widdess-Walsh, P, Wolff, M, Wolking, S, Wu, D, Yamakawa, K, Yang, W, Yapici, Z, Yucesan, E, Zagaglia, S, Zahnert, F, Zara, F, Zhou, W, Zimprich, F, Zsurka, G, and Ali, QZ

Abstract

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.

Published
2023

2. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author

Motelow, JE, Povysil, G, Dhindsa, RS, Stanley, KE, Allen, AS, Feng, Y-CA, Howrigan, DP, Abbott, LE, Tashman, K, Cerrato, F, Cusick, C, Singh, T, Heyne, H, Byrnes, AE, Churchhouse, C, Watts, N, Solomonson, M, Lal, D, Gupta, N, Neale, BM, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Bennett, CA, Leu, C, Leech, SL, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Ali, QZ, Sadoway, TR, Krestel, H, Schaller, A, Papacostas, SS, Kousiappa, I, Tanteles, GA, Christou, Y, Sterbova, K, Vlckova, M, Sedlackova, L, Lassuthova, P, Klein, KM, Rosenow, F, Reif, PS, Knake, S, Neubauer, BA, Zimprich, F, Feucht, M, Reinthaler, EM, Kunz, WS, Zsurka, G, Surges, R, Baumgartner, T, von Wrede, R, Pendziwiat, M, Muhle, H, Rademacher, A, van Baalen, A, von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Muller-Schluter, K, Kluger, G, Haeusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Lauxmann, S, Bosselmann, C, Kegele, J, Hengsbach, C, Rau, S, Steinhoff, BJ, Schulze-Bonhage, A, Borggraefe, I, Schankin, CJ, Schubert-Bast, S, Schreiber, H, Mayer, T, Korinthenberg, R, Brockmann, K, Wolff, M, Dennig, D, Madeleyn, R, Kalviainen, R, Saarela, A, Timonen, O, Linnankivi, T, Lehesjoki, A-E, Rheims, S, Lesca, G, Ryvlin, P, Maillard, L, Valton, L, Derambure, P, Bartolomei, F, Hirsch, E, Michel, V, Chassoux, F, Rees, M, Chung, S-K, Pickrell, WO, Powell, R, Baker, MD, Fonferko-Shadrach, B, Lawthom, C, Anderson, J, Schneider, N, Balestrini, S, Zagaglia, S, Braatz, V, Johnson, MR, Auce, P, Sills, GJ, Baum, LW, Sham, PC, Cherny, SS, Lui, CHT, Delanty, N, Doherty, CP, Shukralla, A, El-Naggar, H, Widdess-Walsh, P, Barisi, N, Canafoglia, L, Franceschetti, S, Castellotti, B, Granata, T, Ragona, F, Zara, F, Iacomino, M, Riva, A, Madia, F, Vari, MS, Salpietro, V, Scala, M, Mancardi, MM, Nobili, L, Amadori, E, Giacomini, T, Bisulli, F, Pippucci, T, Licchetta, L, Minardi, R, Tinuper, P, Muccioli, L, Mostacci, B, Gambardella, A, Labate, A, Annesi, G, Manna, L, Gagliardi, M, Parrini, E, Mei, D, Vetro, A, Bianchini, C, Montomoli, M, Doccini, V, Barba, C, Hirose, S, Ishii, A, Suzuki, T, Inoue, Y, Yamakawa, K, Beydoun, A, Nasreddine, W, Zgheib, NK, Tumiene, B, Utkus, A, Sadleir, LG, King, C, Caglayan, SH, Arslan, M, Yapici, Z, Topaloglu, P, Kara, B, Yis, U, Turkdogan, D, Gundogdu-Eken, A, Bebek, N, Tsai, M-H, Ho, C-J, Lin, C-H, Lin, K-L, Chou, I-J, Poduri, A, Shiedley, BR, Shain, C, Noebels, JL, Goldman, A, Busch, RM, Jehi, L, Najm, IM, Ferguson, L, Khoury, J, Glauser, TA, Clark, PO, Buono, RJ, Ferraro, TN, Sperling, MR, Lo, W, Privitera, M, French, JA, Schachter, S, Kuzniecky, R, Devinsky, O, Hegde, M, Greenberg, DA, Ellis, CA, Goldberg, E, Helbig, KL, Cosico, M, Vaidiswaran, P, Fitch, E, Berkovic, SF, Lerche, H, Lowenstein, DH, Goldstein, DB, Motelow, JE, Povysil, G, Dhindsa, RS, Stanley, KE, Allen, AS, Feng, Y-CA, Howrigan, DP, Abbott, LE, Tashman, K, Cerrato, F, Cusick, C, Singh, T, Heyne, H, Byrnes, AE, Churchhouse, C, Watts, N, Solomonson, M, Lal, D, Gupta, N, Neale, BM, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Bennett, CA, Leu, C, Leech, SL, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Ali, QZ, Sadoway, TR, Krestel, H, Schaller, A, Papacostas, SS, Kousiappa, I, Tanteles, GA, Christou, Y, Sterbova, K, Vlckova, M, Sedlackova, L, Lassuthova, P, Klein, KM, Rosenow, F, Reif, PS, Knake, S, Neubauer, BA, Zimprich, F, Feucht, M, Reinthaler, EM, Kunz, WS, Zsurka, G, Surges, R, Baumgartner, T, von Wrede, R, Pendziwiat, M, Muhle, H, Rademacher, A, van Baalen, A, von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Muller-Schluter, K, Kluger, G, Haeusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Lauxmann, S, Bosselmann, C, Kegele, J, Hengsbach, C, Rau, S, Steinhoff, BJ, Schulze-Bonhage, A, Borggraefe, I, Schankin, CJ, Schubert-Bast, S, Schreiber, H, Mayer, T, Korinthenberg, R, Brockmann, K, Wolff, M, Dennig, D, Madeleyn, R, Kalviainen, R, Saarela, A, Timonen, O, Linnankivi, T, Lehesjoki, A-E, Rheims, S, Lesca, G, Ryvlin, P, Maillard, L, Valton, L, Derambure, P, Bartolomei, F, Hirsch, E, Michel, V, Chassoux, F, Rees, M, Chung, S-K, Pickrell, WO, Powell, R, Baker, MD, Fonferko-Shadrach, B, Lawthom, C, Anderson, J, Schneider, N, Balestrini, S, Zagaglia, S, Braatz, V, Johnson, MR, Auce, P, Sills, GJ, Baum, LW, Sham, PC, Cherny, SS, Lui, CHT, Delanty, N, Doherty, CP, Shukralla, A, El-Naggar, H, Widdess-Walsh, P, Barisi, N, Canafoglia, L, Franceschetti, S, Castellotti, B, Granata, T, Ragona, F, Zara, F, Iacomino, M, Riva, A, Madia, F, Vari, MS, Salpietro, V, Scala, M, Mancardi, MM, Nobili, L, Amadori, E, Giacomini, T, Bisulli, F, Pippucci, T, Licchetta, L, Minardi, R, Tinuper, P, Muccioli, L, Mostacci, B, Gambardella, A, Labate, A, Annesi, G, Manna, L, Gagliardi, M, Parrini, E, Mei, D, Vetro, A, Bianchini, C, Montomoli, M, Doccini, V, Barba, C, Hirose, S, Ishii, A, Suzuki, T, Inoue, Y, Yamakawa, K, Beydoun, A, Nasreddine, W, Zgheib, NK, Tumiene, B, Utkus, A, Sadleir, LG, King, C, Caglayan, SH, Arslan, M, Yapici, Z, Topaloglu, P, Kara, B, Yis, U, Turkdogan, D, Gundogdu-Eken, A, Bebek, N, Tsai, M-H, Ho, C-J, Lin, C-H, Lin, K-L, Chou, I-J, Poduri, A, Shiedley, BR, Shain, C, Noebels, JL, Goldman, A, Busch, RM, Jehi, L, Najm, IM, Ferguson, L, Khoury, J, Glauser, TA, Clark, PO, Buono, RJ, Ferraro, TN, Sperling, MR, Lo, W, Privitera, M, French, JA, Schachter, S, Kuzniecky, R, Devinsky, O, Hegde, M, Greenberg, DA, Ellis, CA, Goldberg, E, Helbig, KL, Cosico, M, Vaidiswaran, P, Fitch, E, Berkovic, SF, Lerche, H, Lowenstein, DH, and Goldstein, DB

Abstract

Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.

Published
2021

3. Polygenic burden in focal and generalized epilepsies

Author

Leu C., Stevelink R., Smith A. W., Goleva S. B., Kanai M., Ferguson L., Campbell C., Kamatani Y., Okada Y., Sisodiya S. M., Cavalleri G. L., Koeleman B. P. C., Lerche H., Jehi L., Davis L. K., Najm I. M., Palotie A., Daly M. J., Busch R. M., Lal D., Feng Y. -C. A., Howrigan D. P., Abbott L. E., Tashman K., Cerrato F., Churchhouse C., Gupta N., Neale B. M., Berkovic S. F., Goldstein D. B., Lowenstein D. H., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E. L., Helbig I., Kwan P., Marson A. G., Petrovski S., Kamalakaran S., Stewart R., Weckhuysen S., Depondt C., Dlugos D. J., Scheffer I. E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B. M., Bellows S. T., Bennett C. A., Johns E. M. C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T. J., Todaro M., Stamberger H., Andrade D. M., Sadoway T. R., Mo K., Krestel H., Gallati S., Papacostas S. S., Kousiappa I., Tanteles G. A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K. M., Rosenow F., Reif P. S., Knake S., Kunz W. S., Zsurka G., Elger C. E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., Van Baalen A., Von Spiczak S., Stephani U., Afawi Z., Korczyn A. D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J. R., Krey I., Weber Y. G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A. F., Steinhoff B. J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C. J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A. -E., Rees M. I., Chung S. -K., Pickrell W. O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M. R., Auce P., Sills G. J., Baum L. W., Sham P. C., Cherny S. S., Lui C. H. T., Barisic N., Delanty N., Doherty C. P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M. S., Mancardi M. M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Muccioli L., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Birute T., Ruta M., Algirdas U., Ruta P., Jurgita G., Ruta S., Sadleir L. G., King C., Mountier E., Caglayan S. H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Sheidley B. R., Shain C., Poduri A., Buono R. J., Ferraro T. N., Sperling M. R., Lo W., Privitera M., French J. A., Schachter S., Kuzniecky R. I., Devinsky O., Hegde M., Khankhanian P., Helbig K. L., Ellis C. A., Spalletta G., Piras F., Gili T., Ciullo V., Leu C., Stevelink R., Smith A.W., Goleva S.B., Kanai M., Ferguson L., Campbell C., Kamatani Y., Okada Y., Sisodiya S.M., Cavalleri G.L., Koeleman B.P.C., Lerche H., Jehi L., Davis L.K., Najm I.M., Palotie A., Daly M.J., Busch R.M., Lal D., Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Churchhouse C., Gupta N., Neale B.M., Berkovic S.F., Goldstein D.B., Lowenstein D.H., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E.L., Helbig I., Kwan P., Marson A.G., Petrovski S., Kamalakaran S., Stewart R., Weckhuysen S., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B.M., Bellows S.T., Bennett C.A., Johns E.M.C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Sadoway T.R., Mo K., Krestel H., Gallati S., Papacostas S.S., Kousiappa I., Tanteles G.A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Kunz W.S., Zsurka G., Elger C.E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., Van Baalen A., Von Spiczak S., Stephani U., Afawi Z., Korczyn A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A.F., Steinhoff B.J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C.J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A.-E., Rees M.I., Chung S.-K., Pickrell W.O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Barisic N., Delanty N., Doherty C.P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M.S., Mancardi M.M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Muccioli L., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Birute T., Ruta M., Algirdas U., Ruta P., Jurgita G., Ruta S., Sadleir L.G., King C., Mountier E., Caglayan S.H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Sheidley B.R., Shain C., Poduri A., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Khankhanian P., Helbig K.L., Ellis C.A., Spalletta G., Piras F., Gili T., Ciullo V., Commission of the European Communities, Medical Research Council (MRC), Tumienė, Birutė, Mameniškienė, Rūta, Utkus, Algirdas, Praninskienė, Rūta, Grikinienė, Jurgita, Samaitienė-Aleknienė, Rūta, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, University of Helsinki, Helsinki Institute of Life Science HiLIFE, and Department of Medical and Clinical Genetics

Subjects
0301 basic medicine, Male, Multifactorial Inheritance, Epi25 Consortium, Databases, Factual, FEATURES, Genome-wide association study, Epilepsies, 3124 Neurology and psychiatry, Cohort Studies, Epilepsy, 0302 clinical medicine, Cost of Illness, 1ST SEIZURE, HISTORY, genetics, POPULATION, 11 Medical and Health Sciences, education.field_of_study, medicine.diagnostic_test, SCORES, Single Nucleotide, Biobank, 3. Good health, 17 Psychology and Cognitive Sciences, Genetic generalized epilepsy, Epilepsy, Generalized, Female, Partial, Cohort study, Human, medicine.medical_specialty, Population, European Continental Ancestry Group, Clinical Neurology, BIOBANK, Polymorphism, Single Nucleotide, epilepsy, genetic generalized epilepsy, common variant risk, Databases, 03 medical and health sciences, Genetic, Internal medicine, medicine, Journal Article, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, Generalized epilepsy, education, SEIZURE RECURRENCE, Factual, METAANALYSIS, Genetic testing, Neurology & Neurosurgery, RISK PREDICTION, Generalized, business.industry, 3112 Neurosciences, Common variant risk, Genetic Variation, Original Articles, medicine.disease, Comorbidity, Cost of Illne, Epilepsies, Partial, Genome-Wide Association Study, 030104 developmental biology, Neurology (clinical), Cohort Studie, business, 030217 neurology & neurosurgery
Abstract

See Hansen and Møller (doi:10.1093/brain/awz318) for a scientific commentary on this article. Using polygenic risk scores from a genome-wide association study in generalized and focal epilepsy, Leu et al. reveal a significantly higher genetic burden for epilepsy in multiple cohorts of people with epilepsy compared to population controls. Quantification of common variant burden may be valuable for epilepsy prognosis and treatment., Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10−15; Cleveland: P = 2.85×10−4; Finnish-ancestry Epi25: P = 1.80×10−4) or population controls (Epi25: P = 2.35×10−70; Cleveland: P = 1.43×10−7; Finnish-ancestry Epi25: P = 3.11×10−4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10−4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10−19; Cleveland: P = 1.69×10−6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10−15; Cleveland: P = 1.39×10−2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls—in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment.

Published
2019
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4. Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17458 subjects

Author

Niestroj, LM, Perez-Palma, E, Howrigan, DP, Zhou, Y, Cheng, F, Saarentaus, E, Nürnberg, P, Stevelink, R, Daly, MJ, Palotie, A, Lal, D, Feng, YCA, Abbott, LE, Tashman, K, Cerrato, F, Churchhouse, C, Gupta, N, Neale, BM, Berkovic, SF, Lerche, H, Goldstein, DB, Lowenstein, DH, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Leu, C, Bennett, CA, Bellows, Susannah, Johns, EMC, MacDonald, A, Shilling, H, Burgess, R, Weckhuysen, D, Bahlo, M, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Sadoway, TR, Mo, K, Krestel, H, Gallati, S, Papacostas, SS, Kousiappa, I, Tanteles, GA, Šterbová, K, Vlcková, M, Sedlácková, L, Laššuthová, P, Martin, K, Rosenow, F, Reif, PS, Knake, S, Kunz, WS, Zsurka, G, Elger, CE, Bauer, J, Rademacher, M, Pendziwiat, M, Muhle, H, Rademacher, A, Van Baalen, A, Von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Müller-Schlüter, K, Kluger, G, Häusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Niestroj, LM, Perez-Palma, E, Howrigan, DP, Zhou, Y, Cheng, F, Saarentaus, E, Nürnberg, P, Stevelink, R, Daly, MJ, Palotie, A, Lal, D, Feng, YCA, Abbott, LE, Tashman, K, Cerrato, F, Churchhouse, C, Gupta, N, Neale, BM, Berkovic, SF, Lerche, H, Goldstein, DB, Lowenstein, DH, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Leu, C, Bennett, CA, Bellows, Susannah, Johns, EMC, MacDonald, A, Shilling, H, Burgess, R, Weckhuysen, D, Bahlo, M, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Sadoway, TR, Mo, K, Krestel, H, Gallati, S, Papacostas, SS, Kousiappa, I, Tanteles, GA, Šterbová, K, Vlcková, M, Sedlácková, L, Laššuthová, P, Martin, K, Rosenow, F, Reif, PS, Knake, S, Kunz, WS, Zsurka, G, Elger, CE, Bauer, J, Rademacher, M, Pendziwiat, M, Muhle, H, Rademacher, A, Van Baalen, A, Von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Müller-Schlüter, K, Kluger, G, Häusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, and Becker, F

Abstract

Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5-3% of patients carry epilepsy-associated CNVs. The character

Published
2020

5. HIV-1 transmission networks across cyprus (2010-2012)

Author

Kostrikis, L.G. Hezka, J. Stylianou, D.C. Kostaki, E. Andreou, M. Kousiappa, I. Paraskevis, D. Demetriades, I.

Subjects
virus diseases
Abstract

A molecular epidemiology study of HIV-1 infection was conducted in one hundred diagnosed and untreated HIV-1-infected patients in Cyprus between 2010 and 2012, representing 65.4% of all the reported HIV-1 infections in Cyprus in this three-year period, using a previously defined enrolment strategy. Eighty-two patients were newly diagnosed (genotypic drug resistance testing within six months from diagnosis), and eighteen patients were HIV-1 diagnosed for a longer period or the diagnosis date was unknown. Phylogenetic trees of the pol sequences obtained in this study with reference sequences indicated that subtypes B and A1 were the most common subtypes present and accounted for 41.0 and 19.0% respectively, followed by subtype C (7.0%), F1 (8.0%), CRF02_AG (4.0%), A2 (2.0%), other circulating recombinant forms (CRFs) (7.0%) and unknown recombinant forms (URFs) (12%). Most of the newly-diagnosed study subjects were Cypriots (63%), males (78%) with median age 39 (Interquartile Range, IQR 33–48) reporting having sex with other men (MSM) (51%). A high rate of clustered transmission of subtype B drug-sensitive strains to reverse transcriptase and protease inhibitors was observed among MSM, twenty-eight out of forty-one MSM study subjects (68.0%) infected were implicated in five transmission clusters, two of which are sub-subtype A1 and three of which are subtype B strains. The two largest MSM subtype B clusters included nine and eight Cypriot men, respectively, living in all major cities in Cyprus. There were only three newly diagnosed patients with transmitted drug resistant HIV-1 strains, one study subject from the United Kingdom infected with subtype B strain and one from Romania with sub-subtype A2 strain, both with PI drug resistance mutation M46L and one from Greece with sub-subtype A1 with nonnucleoside reverse transcriptase inhibitors (NNRTI) drug resistance mutation K103N. © 2018 Kostrikis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Published
2018

6. Transmission of HIV drug resistance and the predicted effect on current first-line regimens in Europe

Author

Hofstra, L.M. Sauvageot, N. Albert, J. Alexiev, I. Garcia, F. Struck, D. Van De Vijver, D.A.M.C. Åsjö, B. Beshkov, D. Coughlan, S. Descamps, D. Griskevicius, A. Hamouda, O. Horban, A. Van Kasteren, M. Kolupajeva, T. Kostrikis, L.G. Liitsola, K. Linka, M. Mor, O. Nielsen, C. Otelea, D. Paraskevis, D. Paredes, R. Poljak, M. Puchhammer-Stöckl, E. Sönnerborg, A. Staneková, D. Stanojevic, M. Van Laethem, K. Zazzi, M. Lepej, S.Z. Boucher, C.A.B. Schmit, J.-C. Wensing, A.M.J. Puchhammer-Stockl, E. Sarcletti, M. Schmied, B. Geit, M. Balluch, G. Vandamme, A.-M. Vercauteren, J. Derdelinckx, I. Sasse, A. Bogaert, M. Ceunen, H. De Roo, A. De Wit, S. Echahidi, F. Fransen, K. Goffard, J.-C. Goubau, P. Goudeseune, E. Yombi, J.-C. Lacor, P. Liesnard, C. Moutschen, M. Pierard, D. Rens, R. Schrooten, Y. Vaira, D. Vandekerckhove, L.P.R. Van Den Heuvel, A. Van Der Gucht, B. Van Ranst, M. Van Wijngaerden, E. Vandercam, B. Vekemans, M. Verhofstede, C. Clumeck, N. Begovac, J. Demetriades, I. Kousiappa, I. Demetriou, V. Hezka, J. Maly, M. Machala, L. Jørgensen, L.B. Gerstoft, J. Mathiesen, L. Pedersen, C. Nielsen, H. Laursen, A. Kvinesdal, B. Ristola, M. Suni, J. Sutinen, J. Assoumou, L. Castor, G. Grude, M. Flandre, P. Storto, A. Kücherer, C. Berg, T. Braun, P. Poggensee, G. Däumer, M. Eberle, J. Heiken, H. Kaiser, R. Knechten, H. Korn, K. Müller, H. Neifer, S. Schmidt, B. Walter, H. Gunsenheimer-Bartmeyer, B. Harrer, T. Hatzakis, A. Zavitsanou, A. Vassilakis, A. Lazanas, M. Chini, M. Lioni, A. Sakka, V. Kourkounti, S. Paparizos, V. Antoniadou, A. Papadopoulos, A. Poulakou, G. Katsarolis, I. Protopapas, K. Chryssos, G. Drimis, S. Gargalianos, P. Xylomenos, G. Lourida, G. Psichogiou, M. Daikos, G.L. Sipsas, N.V. Kontos, A. Gamaletsou, M.N. Koratzanis, G. Sambatakou, E. Mariolis, H. Skoutelis, A. Papastamopoulos, V. Georgiou, O. Panagopoulos, P. Maltezos, E. De Gascun, C. Byrne, C. Duffy, M. Bergin, C. Reidy, D. Farrell, G. Lambert, J. O'Connor, E. Rochford, A. Low, J. Coakely, P. O'Dea, S. Hall, W. Levi, I. Chemtob, D. Grossman, Z. De Luca, A. Balotta, C. Riva, C. Mussini, C. Caramma, I. Capetti, A. Colombo, M.C. Rossi, C. Prati, F. Tramuto, F. Vitale, F. Ciccozzi, M. Angarano, G. Rezza, G. Vasins, O. Lipnickiene, V. Hemmer, R. Arendt, V. Michaux, C. Staub, T. Sequin-Devaux, C. Van Kessel, A. Van Bentum, P.H.M. Brinkman, K. Connell, B.J. Van Der Ende, M.E. Hoepelman, I.M. Kuipers, M. Langebeek, N. Richter, C. Santegoets, R.M.W.J. Schrijnders-Gudde, L. Schuurman, R. Van De Ven, B.J.M. Kran, A.-M.B. Ormaasen, V. Aavitsland, P. Stanczak, J.J. Stanczak, G.P. Firlag-Burkacka, E. Wiercinska-Drapalo, A. Jablonowska, E. Maolepsza, E. Leszczyszyn-Pynka, M. Szata, W. Camacho, R. Palma, C. Borges, F. Paixão, T. Duque, V. Araújo, F. Paraschiv, S. Tudor, A.M. Cernat, R. Chiriac, C. Dumitrescu, F. Prisecariu, L.J. Jevtovic, Dj. Salemovic, D. Stanekova, D. Habekova, M. Chabadová, Z. Drobkova, T. Bukovinova, P. Shunnar, A. Truska, P. Lunar, M. Babic, D. Tomazic, J. Vidmar, L. Vovko, T. Karner, P. Monge, S. Moreno, S. Del Amo, J. Asensi, V. Sirvent, J.L. De Mendoza, C. Delgado, R. Gutiérrez, F. Berenguer, J. Garcia-Bujalance, S. Stella, N. De Los Santos, I. Blanco, J.R. Dalmau, D. Rivero, M. Segura, F. Elías, M.J.P. Alvarez, M. Chueca, N. Rodríguez-Martín, C. Vidal, C. Palomares, J.C. Viciana, I. Viciana, P. Cordoba, J. Aguilera, A. Domingo, P. Galindo, M.J. Miralles, C. Del Pozo, M.A. Ribera, E. Iribarren, J.A. Ruiz, L. De La Torre, J. Vidal, F. Clotet, B. Heidarian, A. Aperia-Peipke, K. Axelsson, M. Mild, M. Karlsson, A. Thalme, A. Navér, L. Bratt, G. Blaxhult, A. Gisslén, M. Svennerholm, B. Björkman, P. Säll, C. Mellgren, Å. Lindholm, A. Kuylenstierna, N. Montelius, R. Azimi, F. Johansson, B. Carlsson, M. Johansson, E. Ljungberg, B. Ekvall, H. Strand, A. Mäkitalo, S. Öberg, S. Holmblad, P. Höfer, M. Holmberg, H. Josefson, P. Ryding, U. Bergbrant, I. SPREAD Program

Abstract

Background. Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001. Methods. Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0. Results. The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%-9.5%) in 2008-2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones. Conclusions. Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affected. © The Author 2015.

Published
2016

7. Primary resistance to integrase strand-transfer inhibitors in Europe

Author

Casadellà, M. van Ham, P.M. Noguera-Julian, M. van Kessel, A. Pou, C. Hofstra, L.M. Santos, J.R. Garcia, F. Struck, D. Alexiev, I. Bakken Kran, A.M. Hoepelman, A.I. Kostrikis, L.G. Somogyi, S. Liitsola, K. Linka, M. Nielsen, C. Otelea, D. Paraskevis, D. Poljak, M. Puchhammer-Stöckl, E. Staneková, D. Stanojevic, M. Van Laethem, K. Zidovec Lepej, S. Clotet, B. Boucher, C.A.B. Paredes, R. Wensing, A.M.J. Puchhammer-Stöckl, E. Sarcletti, M. Schmied, B. Geit, M. Balluch, G. Vandamme, A.M. Vercauteren, J. Derdelinckx, I. Sasse, A. Bogaert, M. Ceunen, H. De Roo, A. De Wit, S. Echahidi, F. Fransen, K. Goffard, J.C. Goubau, P. Goudeseune, E. Yombi, J.C. Lacor, P. Liesnard, C. Moutschen, M. Pierard, D. Rens, R. Schrooten, Y. Vaira, D. Vandekerckhove, L.P. Van den Heuvel, A. Van Der Gucht, B. Van Ranst, M. Van Wijngaerden, E. Vandercam, B. Vekemans, M. Verhofstede, C. Clumeck, N. Van Laethem, K. Beshkov, D. Alexiev, I. Zidovec Lepej, S. Begovac, J. Demetriades, I. Kousiappa, I. Demetriou, V. Hezka, J. Linka, M. Machala, L. Maly, M. Nielsen, C. Jørgensen, L.B. Gerstoft, J. Mathiesen, L. Pedersen, C. Nielsen, H. Laursen, A. Kvinesdal, B. Liitsola, K. Ristola, M. Suni, J. Sutinen, J. Hamouda, O. Kücherer, C. Berg, T. Braun, P. Poggensee, G. Däumer, M. Eberle, J. Heiken, H. Kaiser, R. Knechten, H. Korn, K. Müller, H. Neifer, S. Schmidt, B. Walter, H. Gunsenheimer-Bartmeyer, B. Harrer, T. Paraskevis, D. Hatzakis, A. Magiorkinis, E. Hatzitheodorou, E. Haida, C. Zavitsanou, A. Magiorkinis, G. Lazanas, M. Chini, M. Magafas, N. Tsogas, N. Paparizos, V. Kourkounti, S. Antoniadou, A. Papadopoulos, A. Panagopoulos, P. Poulakou, G. Sakka, V. Chryssos, G. Drimis, S. Gargalianos, P. Lelekis, M. Chilomenos, G. Psichogiou, M. Daikos, G.L. Sabatakou, H. Panos, G. Haratsis, G. Kordossis, T. Kontos, A. Koratzanis, G. Theodoridou, M. Mostrou, G. Spoulou, V. Schmit, J.C. Struck, D. Hemmer, R. Arendt, V. Staub, T. Schneider, F. Roman, F. Wensing, A.M. Boucher, C.A. van de Vijver, D.A. van Kessel, A. van, P.H. Brinkman, K. Op de, E.L. van der Ende, M.E. Hoepelman, I.M. van Kasteren, M. Juttmann, J. Kuipers, M. Langebeek, N. Richter, C. Santegoets, R.M. Schrijnders-Gudde, L. Schuurman, R. van de Ven, B.J. Åsjö, B. Bakken, A.M. Ormaasen, V. Aavitsland, P. Otelea, D. Paraschiv, S. Tudor, A.M. Jevtovic, D. Salemovic, D. Stanekova, D. Habekova, M. Mokras, M. Truska, P. Poljak, M. Lunar, M. Babic, D. Tomazic, J. Vidmar, L. Vovko, T. Karner, P. Clotet, B. Garcia, F. Domingo, P. Galindo, M.J. Miralles, C. Del, M.A. Ribera, E. Iribarren, J.A. Ruiz, L. de la Torre, J. Vidal, F. Garcia, F. Paredes, R. on behalf of the SPREAD programme

Abstract

Objectives: The objective of this study was to define the natural genotypic variation of the HIV-1 integrase gene across Europe for epidemiological surveillance of integrase strand-transfer inhibitor (InSTI) resistance. Methods: This was a multicentre, cross-sectional study within the European SPREAD HIV resistance surveillance programme. A representative set of 300 samples was selected from 1950 naive HIV-positive subjects newly diagnosed in 2006-07. The prevalence of InSTI resistance was evaluated using quality-controlled baseline population sequencing of integrase. Signature raltegravir, elvitegravir and dolutegravir resistance mutations were defined according to the IAS-USA 2014 list. In addition, all integrase substitutions relative to HXB2 were identified, including those with a Stanford HIVdb score=10 to at least one InSTI. To rule out circulation of minority InSTIresistant HIV, 65 samples were selected for 454 integrase sequencing. Results: For the population sequencing analysis, 278 samples were retrieved and successfully analysed. No signature resistance mutations to any of the InSTIswere detected. Eleven (4%) subjects hadmutations at resistance-associated positions with an HIVdb score =10. Of the 56 samples successfully analysed with 454 sequencing, no InSTI signature mutationsweredetected, whereas integrase substitutionswithanHIVdbscore=10were found in8(14.3%) individuals. Conclusions:No signature InSTI-resistant variantswere circulating in Europe before the introduction of InSTIs. However, polymorphisms contributing to InSTI resistancewere not rare. As InSTI use becomes more widespread, continuous surveillance of primary InSTI resistance is warranted. These data will be key to modelling the kinetics of InSTI resistance transmission in Europe in the coming years. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Published
2015

8. Transmission of HIV drug resistance and the predicted effect on current first-line regimens in Europe

Author

Hofstra, L. Marije, Sauvageot, Nicolas, Albert, Jan, Alexiev, Ivailo, Garcia, Federico, Struck, Daniel, Van De Vijver, David A M C, Åsjö, Birgitta, Beshkov, Danail, Coughlan, Suzie, Descamps, Diane, Griskevicius, Algirdas, Hamouda, Osamah, Horban, Andrzej, Van Kasteren, Marjo, Kolupajeva, Tatjana, Kostrikis, Leontios G., Liitsola, Kirsi, Linka, Marek, Mor, Orna, Nielsen, Claus, Otelea, Dan, Paraskevis, Dimitrios, Paredes, Roger, Poljak, Mario, Puchhammer-Stöckl, Elisabeth, Sönnerborg, Anders, Staneková, Danica, Stanojevic, Maja, Van Laethem, Kristel, Zazzi, Maurizio, Lepej, Snjezana Zidovec, Boucher, Charles A B, Schmit, Jean Claude, Wensing, Annemarie M J, Puchhammer-Stockl, E., Sarcletti, M., Schmied, B., Geit, M., Balluch, G., Vandamme, A. M., Vercauteren, J., Derdelinckx, I., Sasse, A., Bogaert, M., Ceunen, H., De Roo, A., De Wit, S., Echahidi, F., Fransen, K., Goffard, J. C., Goubau, P., Goudeseune, E., Yombi, J. C., Lacor, P., Liesnard, C., Moutschen, M., Pierard, D., Rens, R., Schrooten, Y., Vaira, D., Vandekerckhove, L. P R, Van Den Heuvel, A., Van Der Gucht, B., Van Ranst, M., Van Wijngaerden, E., Vandercam, B., Vekemans, M., Verhofstede, C., Clumeck, N., Van Laethem, K., Beshkov, D., Alexiev, I., Lepej, S. Zidovec, Begovac, J., Demetriades, I., Kousiappa, I., Demetriou, V., Hezka, J., Linka, M., Maly, M., Machala, L., Nielsen, C., Jørgensen, L. B., Gerstoft, J., Mathiesen, L., Pedersen, C., Nielsen, H., Laursen, A., Kvinesdal, B., Liitsola, K., Ristola, M., Suni, J., Sutinen, J., Descamps, D., Assoumou, L., Castor, G., Grude, M., Flandre, P., Storto, A., Hamouda, O., Kücherer, C., Berg, T., Braun, P., Poggensee, G., Däumer, M., Eberle, J., Heiken, H., Kaiser, R., Knechten, H., Korn, K., Müller, H., Neifer, S., Schmidt, B., Walter, H., Gunsenheimer-Bartmeyer, B., Harrer, T., Paraskevis, D., Hatzakis, A., Zavitsanou, A., Vassilakis, A., Lazanas, M., Chini, M., Lioni, A., Sakka, V., Kourkounti, S., Paparizos, V., Antoniadou, A., Papadopoulos, A., Poulakou, G., Katsarolis, I., Protopapas, K., Chryssos, G., Drimis, S., Gargalianos, P., Xylomenos, G., Lourida, G., Psichogiou, M., Daikos, G. L., Sipsas, N. V., Kontos, A., Gamaletsou, M. N., Koratzanis, G., Sambatakou, E., Mariolis, H., Skoutelis, A., Papastamopoulos, V., Georgiou, O., Panagopoulos, P., Maltezos, E., Coughlan, S., De Gascun, C., Byrne, C., Duffy, M., Bergin, C., Reidy, D., Farrell, G., Lambert, J., O'Connor, E., Rochford, A., Low, J., Coakely, P., O'Dea, S., Hall, W., Mor, O., Levi, I., Chemtob, D., Grossman, Z., Zazzi, M., De Luca, A., Balotta, C., Riva, C., Mussini, C., Caramma, I., Capetti, A., Colombo, M. C., Rossi, C., Prati, F., Tramuto, F., Vitale, F., Ciccozzi, M., Angarano, G., Rezza, G., Kolupajeva, T., Vasins, O., Griskevicius, A., Lipnickiene, V., Schmit, J. C., Struck, D., Sauvageot, N., Hemmer, R., Arendt, V., Michaux, C., Staub, T., Sequin-Devaux, C., Wensing, A. M J, Boucher, C. A B, Van Kessel, A., Van Bentum, P. H M, Brinkman, K., Connell, B. J., Van Der Ende, M. E., Hoepelman, I. M., Van Kasteren, M., Kuipers, M., Langebeek, N., Richter, C., Santegoets, R. M W J, Schrijnders-Gudde, L., Schuurman, R., Van De Ven, B. J M, Åsjö, B., Kran, A. M Bakken, Ormaasen, V., Aavitsland, P., Horban, A., Stanczak, J. J., Stanczak, G. P., Firlag-Burkacka, E., Wiercinska-Drapalo, A., Jablonowska, E., Maolepsza, E., Leszczyszyn-Pynka, M., Szata, W., Camacho, R., Palma, C., Borges, F., Paixão, T., Duque, V., Araújo, F., Otelea, D., Paraschiv, S., Tudor, A. M., Cernat, R., Chiriac, C., Dumitrescu, F., Prisecariu, L. J., Stanojevic, M., Jevtovic, Dj, Salemovic, D., Stanekova, D., Habekova, M., Chabadová, Z., Drobkova, T., Bukovinova, P., Shunnar, A., Truska, P., Poljak, M., Lunar, M., Babic, D., Tomazic, J., Vidmar, L., Vovko, T., Karner, P., Garcia, F., Paredes, R., Monge, S., Moreno, S., Del Amo, J., Asensi, V., Sirvent, J. L., De Mendoza, C., Delgado, R., Gutiérrez, F., Berenguer, J., Garcia-Bujalance, S., Stella, N., De Los Santos, I., Blanco, J. R., Dalmau, D., Rivero, M., Segura, F., Elías, M. J Pérez, Alvarez, M., Chueca, N., Rodríguez-Martín, C., Vidal, C., Palomares, J. C., Viciana, I., Viciana, P., Cordoba, J., Aguilera, A., Domingo, P., Galindo, M. J., Miralles, C., Del Pozo, M. A., Ribera, E., Iribarren, J. A., Ruiz, L., De La Torre, J., Vidal, F., Clotet, B., Albert, J., Heidarian, A., Aperia-Peipke, K., Axelsson, M., Mild, M., Karlsson, A., Sönnerborg, A., Thalme, A., Navér, L., Bratt, G., Blaxhult, A., Gisslén, M., Svennerholm, B., Bergbrant, I., Björkman, P., Säll, C., Mellgren, Lindholm, A., Kuylenstierna, N., Montelius, R., Azimi, F., Johansson, B., Carlsson, M., Johansson, E., Ljungberg, B., Ekvall, H., Strand, A., Mäkitalo, S., Öberg, S., Holmblad, P., Höfer, M., Holmberg, H., Josefson, P., Ryding, U., Hofstra, L. Marije, Sauvageot, Nicolas, Albert, Jan, Alexiev, Ivailo, Garcia, Federico, Struck, Daniel, Van De Vijver, David A M C, Åsjö, Birgitta, Beshkov, Danail, Coughlan, Suzie, Descamps, Diane, Griskevicius, Algirdas, Hamouda, Osamah, Horban, Andrzej, Van Kasteren, Marjo, Kolupajeva, Tatjana, Kostrikis, Leontios G., Liitsola, Kirsi, Linka, Marek, Mor, Orna, Nielsen, Claus, Otelea, Dan, Paraskevis, Dimitrios, Paredes, Roger, Poljak, Mario, Puchhammer-Stöckl, Elisabeth, Sönnerborg, Anders, Staneková, Danica, Stanojevic, Maja, Van Laethem, Kristel, Zazzi, Maurizio, Lepej, Snjezana Zidovec, Boucher, Charles A B, Schmit, Jean Claude, Wensing, Annemarie M J, Puchhammer-Stockl, E., Sarcletti, M., Schmied, B., Geit, M., Balluch, G., Vandamme, A. M., Vercauteren, J., Derdelinckx, I., Sasse, A., Bogaert, M., Ceunen, H., De Roo, A., De Wit, S., Echahidi, F., Fransen, K., Goffard, J. C., Goubau, P., Goudeseune, E., Yombi, J. C., Lacor, P., Liesnard, C., Moutschen, M., Pierard, D., Rens, R., Schrooten, Y., Vaira, D., Vandekerckhove, L. P R, Van Den Heuvel, A., Van Der Gucht, B., Van Ranst, M., Van Wijngaerden, E., Vandercam, B., Vekemans, M., Verhofstede, C., Clumeck, N., Van Laethem, K., Beshkov, D., Alexiev, I., Lepej, S. Zidovec, Begovac, J., Demetriades, I., Kousiappa, I., Demetriou, V., Hezka, J., Linka, M., Maly, M., Machala, L., Nielsen, C., Jørgensen, L. B., Gerstoft, J., Mathiesen, L., Pedersen, C., Nielsen, H., Laursen, A., Kvinesdal, B., Liitsola, K., Ristola, M., Suni, J., Sutinen, J., Descamps, D., Assoumou, L., Castor, G., Grude, M., Flandre, P., Storto, A., Hamouda, O., Kücherer, C., Berg, T., Braun, P., Poggensee, G., Däumer, M., Eberle, J., Heiken, H., Kaiser, R., Knechten, H., Korn, K., Müller, H., Neifer, S., Schmidt, B., Walter, H., Gunsenheimer-Bartmeyer, B., Harrer, T., Paraskevis, D., Hatzakis, A., Zavitsanou, A., Vassilakis, A., Lazanas, M., Chini, M., Lioni, A., Sakka, V., Kourkounti, S., Paparizos, V., Antoniadou, A., Papadopoulos, A., Poulakou, G., Katsarolis, I., Protopapas, K., Chryssos, G., Drimis, S., Gargalianos, P., Xylomenos, G., Lourida, G., Psichogiou, M., Daikos, G. L., Sipsas, N. V., Kontos, A., Gamaletsou, M. N., Koratzanis, G., Sambatakou, E., Mariolis, H., Skoutelis, A., Papastamopoulos, V., Georgiou, O., Panagopoulos, P., Maltezos, E., Coughlan, S., De Gascun, C., Byrne, C., Duffy, M., Bergin, C., Reidy, D., Farrell, G., Lambert, J., O'Connor, E., Rochford, A., Low, J., Coakely, P., O'Dea, S., Hall, W., Mor, O., Levi, I., Chemtob, D., Grossman, Z., Zazzi, M., De Luca, A., Balotta, C., Riva, C., Mussini, C., Caramma, I., Capetti, A., Colombo, M. C., Rossi, C., Prati, F., Tramuto, F., Vitale, F., Ciccozzi, M., Angarano, G., Rezza, G., Kolupajeva, T., Vasins, O., Griskevicius, A., Lipnickiene, V., Schmit, J. C., Struck, D., Sauvageot, N., Hemmer, R., Arendt, V., Michaux, C., Staub, T., Sequin-Devaux, C., Wensing, A. M J, Boucher, C. A B, Van Kessel, A., Van Bentum, P. H M, Brinkman, K., Connell, B. J., Van Der Ende, M. E., Hoepelman, I. M., Van Kasteren, M., Kuipers, M., Langebeek, N., Richter, C., Santegoets, R. M W J, Schrijnders-Gudde, L., Schuurman, R., Van De Ven, B. J M, Åsjö, B., Kran, A. M Bakken, Ormaasen, V., Aavitsland, P., Horban, A., Stanczak, J. J., Stanczak, G. P., Firlag-Burkacka, E., Wiercinska-Drapalo, A., Jablonowska, E., Maolepsza, E., Leszczyszyn-Pynka, M., Szata, W., Camacho, R., Palma, C., Borges, F., Paixão, T., Duque, V., Araújo, F., Otelea, D., Paraschiv, S., Tudor, A. M., Cernat, R., Chiriac, C., Dumitrescu, F., Prisecariu, L. J., Stanojevic, M., Jevtovic, Dj, Salemovic, D., Stanekova, D., Habekova, M., Chabadová, Z., Drobkova, T., Bukovinova, P., Shunnar, A., Truska, P., Poljak, M., Lunar, M., Babic, D., Tomazic, J., Vidmar, L., Vovko, T., Karner, P., Garcia, F., Paredes, R., Monge, S., Moreno, S., Del Amo, J., Asensi, V., Sirvent, J. L., De Mendoza, C., Delgado, R., Gutiérrez, F., Berenguer, J., Garcia-Bujalance, S., Stella, N., De Los Santos, I., Blanco, J. R., Dalmau, D., Rivero, M., Segura, F., Elías, M. J Pérez, Alvarez, M., Chueca, N., Rodríguez-Martín, C., Vidal, C., Palomares, J. C., Viciana, I., Viciana, P., Cordoba, J., Aguilera, A., Domingo, P., Galindo, M. J., Miralles, C., Del Pozo, M. A., Ribera, E., Iribarren, J. A., Ruiz, L., De La Torre, J., Vidal, F., Clotet, B., Albert, J., Heidarian, A., Aperia-Peipke, K., Axelsson, M., Mild, M., Karlsson, A., Sönnerborg, A., Thalme, A., Navér, L., Bratt, G., Blaxhult, A., Gisslén, M., Svennerholm, B., Bergbrant, I., Björkman, P., Säll, C., Mellgren, Lindholm, A., Kuylenstierna, N., Montelius, R., Azimi, F., Johansson, B., Carlsson, M., Johansson, E., Ljungberg, B., Ekvall, H., Strand, A., Mäkitalo, S., Öberg, S., Holmblad, P., Höfer, M., Holmberg, H., Josefson, P., and Ryding, U.

Published
2016

9. Transmission of HIV drug resistance and the predicted effect on current first-line regimens in Europe

Author

MMB opleiding Arts microbioloog, MMB Medische Staf, Infection & Immunity, Onderzoek Bob Oranje, Brain, Cardiovasculaire Epi Team 1, MMB Research line 3a, MS Infectieziekten, Circulatory Health, MMB Staf diagnostiek, Hofstra, L. Marije, Sauvageot, Nicolas, Albert, Jan, Alexiev, Ivailo, Garcia, Federico, Struck, Daniel, Van De Vijver, David A M C, Åsjö, Birgitta, Beshkov, Danail, Coughlan, Suzie, Descamps, Diane, Griskevicius, Algirdas, Hamouda, Osamah, Horban, Andrzej, Van Kasteren, Marjo, Kolupajeva, Tatjana, Kostrikis, Leontios G., Liitsola, Kirsi, Linka, Marek, Mor, Orna, Nielsen, Claus, Otelea, Dan, Paraskevis, Dimitrios, Paredes, Roger, Poljak, Mario, Puchhammer-Stöckl, Elisabeth, Sönnerborg, Anders, Staneková, Danica, Stanojevic, Maja, Van Laethem, Kristel, Zazzi, Maurizio, Lepej, Snjezana Zidovec, Boucher, Charles A B, Schmit, Jean Claude, Wensing, Annemarie M J, Puchhammer-Stockl, E., Sarcletti, M., Schmied, B., Geit, M., Balluch, G., Vandamme, A. M., Vercauteren, J., Derdelinckx, I., Sasse, A., Bogaert, M., Ceunen, H., De Roo, A., De Wit, S., Echahidi, F., Fransen, K., Goffard, J. C., Goubau, P., Goudeseune, E., Yombi, J. C., Lacor, P., Liesnard, C., Moutschen, M., Pierard, D., Rens, R., Schrooten, Y., Vaira, D., Vandekerckhove, L. P R, Van Den Heuvel, A., Van Der Gucht, B., Van Ranst, M., Van Wijngaerden, E., Vandercam, B., Vekemans, M., Verhofstede, C., Clumeck, N., Van Laethem, K., Beshkov, D., Alexiev, I., Lepej, S. Zidovec, Begovac, J., Demetriades, I., Kousiappa, I., Demetriou, V., Hezka, J., Linka, M., Maly, M., Machala, L., Nielsen, C., Jørgensen, L. B., Gerstoft, J., Mathiesen, L., Pedersen, C., Nielsen, H., Laursen, A., Kvinesdal, B., Liitsola, K., Ristola, M., Suni, J., Sutinen, J., Descamps, D., Assoumou, L., Castor, G., Grude, M., Flandre, P., Storto, A., Hamouda, O., Kücherer, C., Berg, T., Braun, P., Poggensee, G., Däumer, M., Eberle, J., Heiken, H., Kaiser, R., Knechten, H., Korn, K., Müller, H., Neifer, S., Schmidt, B., Walter, H., Gunsenheimer-Bartmeyer, B., Harrer, T., Paraskevis, D., Hatzakis, A., Zavitsanou, A., Vassilakis, A., Lazanas, M., Chini, M., Lioni, A., Sakka, V., Kourkounti, S., Paparizos, V., Antoniadou, A., Papadopoulos, A., Poulakou, G., Katsarolis, I., Protopapas, K., Chryssos, G., Drimis, S., Gargalianos, P., Xylomenos, G., Lourida, G., Psichogiou, M., Daikos, G. L., Sipsas, N. V., Kontos, A., Gamaletsou, M. N., Koratzanis, G., Sambatakou, E., Mariolis, H., Skoutelis, A., Papastamopoulos, V., Georgiou, O., Panagopoulos, P., Maltezos, E., Coughlan, S., De Gascun, C., Byrne, C., Duffy, M., Bergin, C., Reidy, D., Farrell, G., Lambert, J., O'Connor, E., Rochford, A., Low, J., Coakely, P., O'Dea, S., Hall, W., Mor, O., Levi, I., Chemtob, D., Grossman, Z., Zazzi, M., De Luca, A., Balotta, C., Riva, C., Mussini, C., Caramma, I., Capetti, A., Colombo, M. C., Rossi, C., Prati, F., Tramuto, F., Vitale, F., Ciccozzi, M., Angarano, G., Rezza, G., Kolupajeva, T., Vasins, O., Griskevicius, A., Lipnickiene, V., Schmit, J. C., Struck, D., Sauvageot, N., Hemmer, R., Arendt, V., Michaux, C., Staub, T., Sequin-Devaux, C., Wensing, A. M J, Boucher, C. A B, Van Kessel, A., Van Bentum, P. H M, Brinkman, K., Connell, B. J., Van Der Ende, M. E., Hoepelman, I. M., Van Kasteren, M., Kuipers, M., Langebeek, N., Richter, C., Santegoets, R. M W J, Schrijnders-Gudde, L., Schuurman, R., Van De Ven, B. J M, Åsjö, B., Kran, A. M Bakken, Ormaasen, V., Aavitsland, P., Horban, A., Stanczak, J. J., Stanczak, G. P., Firlag-Burkacka, E., Wiercinska-Drapalo, A., Jablonowska, E., Maolepsza, E., Leszczyszyn-Pynka, M., Szata, W., Camacho, R., Palma, C., Borges, F., Paixão, T., Duque, V., Araújo, F., Otelea, D., Paraschiv, S., Tudor, A. M., Cernat, R., Chiriac, C., Dumitrescu, F., Prisecariu, L. J., Stanojevic, M., Jevtovic, Dj, Salemovic, D., Stanekova, D., Habekova, M., Chabadová, Z., Drobkova, T., Bukovinova, P., Shunnar, A., Truska, P., Poljak, M., Lunar, M., Babic, D., Tomazic, J., Vidmar, L., Vovko, T., Karner, P., Garcia, F., Paredes, R., Monge, S., Moreno, S., Del Amo, J., Asensi, V., Sirvent, J. L., De Mendoza, C., Delgado, R., Gutiérrez, F., Berenguer, J., Garcia-Bujalance, S., Stella, N., De Los Santos, I., Blanco, J. R., Dalmau, D., Rivero, M., Segura, F., Elías, M. J Pérez, Alvarez, M., Chueca, N., Rodríguez-Martín, C., Vidal, C., Palomares, J. C., Viciana, I., Viciana, P., Cordoba, J., Aguilera, A., Domingo, P., Galindo, M. J., Miralles, C., Del Pozo, M. A., Ribera, E., Iribarren, J. A., Ruiz, L., De La Torre, J., Vidal, F., Clotet, B., Albert, J., Heidarian, A., Aperia-Peipke, K., Axelsson, M., Mild, M., Karlsson, A., Sönnerborg, A., Thalme, A., Navér, L., Bratt, G., Blaxhult, A., Gisslén, M., Svennerholm, B., Bergbrant, I., Björkman, P., Säll, C., Mellgren, Lindholm, A., Kuylenstierna, N., Montelius, R., Azimi, F., Johansson, B., Carlsson, M., Johansson, E., Ljungberg, B., Ekvall, H., Strand, A., Mäkitalo, S., Öberg, S., Holmblad, P., Höfer, M., Holmberg, H., Josefson, P., Ryding, U., MMB opleiding Arts microbioloog, MMB Medische Staf, Infection & Immunity, Onderzoek Bob Oranje, Brain, Cardiovasculaire Epi Team 1, MMB Research line 3a, MS Infectieziekten, Circulatory Health, MMB Staf diagnostiek, Hofstra, L. Marije, Sauvageot, Nicolas, Albert, Jan, Alexiev, Ivailo, Garcia, Federico, Struck, Daniel, Van De Vijver, David A M C, Åsjö, Birgitta, Beshkov, Danail, Coughlan, Suzie, Descamps, Diane, Griskevicius, Algirdas, Hamouda, Osamah, Horban, Andrzej, Van Kasteren, Marjo, Kolupajeva, Tatjana, Kostrikis, Leontios G., Liitsola, Kirsi, Linka, Marek, Mor, Orna, Nielsen, Claus, Otelea, Dan, Paraskevis, Dimitrios, Paredes, Roger, Poljak, Mario, Puchhammer-Stöckl, Elisabeth, Sönnerborg, Anders, Staneková, Danica, Stanojevic, Maja, Van Laethem, Kristel, Zazzi, Maurizio, Lepej, Snjezana Zidovec, Boucher, Charles A B, Schmit, Jean Claude, Wensing, Annemarie M J, Puchhammer-Stockl, E., Sarcletti, M., Schmied, B., Geit, M., Balluch, G., Vandamme, A. M., Vercauteren, J., Derdelinckx, I., Sasse, A., Bogaert, M., Ceunen, H., De Roo, A., De Wit, S., Echahidi, F., Fransen, K., Goffard, J. C., Goubau, P., Goudeseune, E., Yombi, J. C., Lacor, P., Liesnard, C., Moutschen, M., Pierard, D., Rens, R., Schrooten, Y., Vaira, D., Vandekerckhove, L. P R, Van Den Heuvel, A., Van Der Gucht, B., Van Ranst, M., Van Wijngaerden, E., Vandercam, B., Vekemans, M., Verhofstede, C., Clumeck, N., Van Laethem, K., Beshkov, D., Alexiev, I., Lepej, S. Zidovec, Begovac, J., Demetriades, I., Kousiappa, I., Demetriou, V., Hezka, J., Linka, M., Maly, M., Machala, L., Nielsen, C., Jørgensen, L. B., Gerstoft, J., Mathiesen, L., Pedersen, C., Nielsen, H., Laursen, A., Kvinesdal, B., Liitsola, K., Ristola, M., Suni, J., Sutinen, J., Descamps, D., Assoumou, L., Castor, G., Grude, M., Flandre, P., Storto, A., Hamouda, O., Kücherer, C., Berg, T., Braun, P., Poggensee, G., Däumer, M., Eberle, J., Heiken, H., Kaiser, R., Knechten, H., Korn, K., Müller, H., Neifer, S., Schmidt, B., Walter, H., Gunsenheimer-Bartmeyer, B., Harrer, T., Paraskevis, D., Hatzakis, A., Zavitsanou, A., Vassilakis, A., Lazanas, M., Chini, M., Lioni, A., Sakka, V., Kourkounti, S., Paparizos, V., Antoniadou, A., Papadopoulos, A., Poulakou, G., Katsarolis, I., Protopapas, K., Chryssos, G., Drimis, S., Gargalianos, P., Xylomenos, G., Lourida, G., Psichogiou, M., Daikos, G. L., Sipsas, N. V., Kontos, A., Gamaletsou, M. N., Koratzanis, G., Sambatakou, E., Mariolis, H., Skoutelis, A., Papastamopoulos, V., Georgiou, O., Panagopoulos, P., Maltezos, E., Coughlan, S., De Gascun, C., Byrne, C., Duffy, M., Bergin, C., Reidy, D., Farrell, G., Lambert, J., O'Connor, E., Rochford, A., Low, J., Coakely, P., O'Dea, S., Hall, W., Mor, O., Levi, I., Chemtob, D., Grossman, Z., Zazzi, M., De Luca, A., Balotta, C., Riva, C., Mussini, C., Caramma, I., Capetti, A., Colombo, M. C., Rossi, C., Prati, F., Tramuto, F., Vitale, F., Ciccozzi, M., Angarano, G., Rezza, G., Kolupajeva, T., Vasins, O., Griskevicius, A., Lipnickiene, V., Schmit, J. C., Struck, D., Sauvageot, N., Hemmer, R., Arendt, V., Michaux, C., Staub, T., Sequin-Devaux, C., Wensing, A. M J, Boucher, C. A B, Van Kessel, A., Van Bentum, P. H M, Brinkman, K., Connell, B. J., Van Der Ende, M. E., Hoepelman, I. M., Van Kasteren, M., Kuipers, M., Langebeek, N., Richter, C., Santegoets, R. M W J, Schrijnders-Gudde, L., Schuurman, R., Van De Ven, B. J M, Åsjö, B., Kran, A. M Bakken, Ormaasen, V., Aavitsland, P., Horban, A., Stanczak, J. J., Stanczak, G. P., Firlag-Burkacka, E., Wiercinska-Drapalo, A., Jablonowska, E., Maolepsza, E., Leszczyszyn-Pynka, M., Szata, W., Camacho, R., Palma, C., Borges, F., Paixão, T., Duque, V., Araújo, F., Otelea, D., Paraschiv, S., Tudor, A. M., Cernat, R., Chiriac, C., Dumitrescu, F., Prisecariu, L. J., Stanojevic, M., Jevtovic, Dj, Salemovic, D., Stanekova, D., Habekova, M., Chabadová, Z., Drobkova, T., Bukovinova, P., Shunnar, A., Truska, P., Poljak, M., Lunar, M., Babic, D., Tomazic, J., Vidmar, L., Vovko, T., Karner, P., Garcia, F., Paredes, R., Monge, S., Moreno, S., Del Amo, J., Asensi, V., Sirvent, J. L., De Mendoza, C., Delgado, R., Gutiérrez, F., Berenguer, J., Garcia-Bujalance, S., Stella, N., De Los Santos, I., Blanco, J. R., Dalmau, D., Rivero, M., Segura, F., Elías, M. J Pérez, Alvarez, M., Chueca, N., Rodríguez-Martín, C., Vidal, C., Palomares, J. C., Viciana, I., Viciana, P., Cordoba, J., Aguilera, A., Domingo, P., Galindo, M. J., Miralles, C., Del Pozo, M. A., Ribera, E., Iribarren, J. A., Ruiz, L., De La Torre, J., Vidal, F., Clotet, B., Albert, J., Heidarian, A., Aperia-Peipke, K., Axelsson, M., Mild, M., Karlsson, A., Sönnerborg, A., Thalme, A., Navér, L., Bratt, G., Blaxhult, A., Gisslén, M., Svennerholm, B., Bergbrant, I., Björkman, P., Säll, C., Mellgren, Lindholm, A., Kuylenstierna, N., Montelius, R., Azimi, F., Johansson, B., Carlsson, M., Johansson, E., Ljungberg, B., Ekvall, H., Strand, A., Mäkitalo, S., Öberg, S., Holmblad, P., Höfer, M., Holmberg, H., Josefson, P., and Ryding, U.

Published
2016

10. Transmission of HIV drug resistance and the predicted effect on current first-line regimens in Europe

Author

Universitat Rovira i Virgili, Hofstra LM, Sauvageot N, Albert J, Alexiev I, Garcia F, Struck D, Van de Vijver DAMC, Åsjö B, Beshkov D, Coughlan S, Descamps D, Griskevicius A, Hamouda O, Horban A, Van Kasteren M, Kolupajeva T, Kostrikis LG, Liitsola K, Linka M, Mor O, Nielsen C, Otelea D, Paraskevis D, Paredes R, Poljak M, Puchhammer-Stöckl E, Sönnerborg A, Staneková D, Stanojevic M, Van Laethem K, Zazzi M, Zidovec Lepej S, Boucher CAB, Schmit JC, Wensing AMJ,, Puchhammer-Stockl E, Sarcletti M, Schmied B, Geit M, Balluch G, Vandamme AM, Vercauteren J, Derdelinckx I, Sasse A, Bogaert M, Ceunen H, De Roo A, De Wit S, Echahidi F, Fransen K, Goffard JC, Goubau P, Goudeseune E, Yombi JC, Lacor P, Liesnard C, Moutschen M, Pierard D, Rens R, Schrooten Y, Vaira D, Vandekerckhove LPR, Van den Heuvel A, Van Der Gucht B, Van Ranst M, Van Wijngaerden E, Vandercam B, Vekemans M, Verhofstede C, Clumeck N, Lepej SZ, Begovac J, Kostrikis L, Demetriades I, Kousiappa I, Demetriou V, Hezka J, Maly M, Machala L, Jørgensen LB, Gerstoft J, Mathiesen L, Pedersen C, Nielsen H, Laursen A, Kvinesdal B, Ristola M, Suni J, Sutinen J, Assoumou L, Castor G, Grude M, Flandre P, Storto A, Kücherer C, Berg T, Braun P, Poggensee G, Däumer M, Eberle J, Heiken H, Kaiser R, Knechten H, Korn K, Müller H, Neifer S, Schmidt B, Walter H, Gunsenheimer-Bartmeyer B, Harrer T, Hatzakis A, Zavitsanou A, Vassilakis A, Lazanas M, Chini M, Lioni A, Sakka V, Kourkounti S, Paparizos V, Antoniadou A, Papadopoulos A, Poulakou G, Katsarolis I, Protopapas K, Chryssos G, Drimis S, Gargalianos P, Xylomenos G, Lourida G, Psichogiou M, Daikos GL, Sipsas NV, Kontos A, Gamaletsou MN, Koratzanis G, Sambatakou H, Mariolis H, Skoutelis A, Papastamopoulos V, Georgiou O, Panagopoulos P, Maltezos E, De Gascun C, Byrne C, Duffy M, Bergin C, Reidy D, Farrell G, Lamber, Universitat Rovira i Virgili, and Hofstra LM, Sauvageot N, Albert J, Alexiev I, Garcia F, Struck D, Van de Vijver DAMC, Åsjö B, Beshkov D, Coughlan S, Descamps D, Griskevicius A, Hamouda O, Horban A, Van Kasteren M, Kolupajeva T, Kostrikis LG, Liitsola K, Linka M, Mor O, Nielsen C, Otelea D, Paraskevis D, Paredes R, Poljak M, Puchhammer-Stöckl E, Sönnerborg A, Staneková D, Stanojevic M, Van Laethem K, Zazzi M, Zidovec Lepej S, Boucher CAB, Schmit JC, Wensing AMJ,, Puchhammer-Stockl E, Sarcletti M, Schmied B, Geit M, Balluch G, Vandamme AM, Vercauteren J, Derdelinckx I, Sasse A, Bogaert M, Ceunen H, De Roo A, De Wit S, Echahidi F, Fransen K, Goffard JC, Goubau P, Goudeseune E, Yombi JC, Lacor P, Liesnard C, Moutschen M, Pierard D, Rens R, Schrooten Y, Vaira D, Vandekerckhove LPR, Van den Heuvel A, Van Der Gucht B, Van Ranst M, Van Wijngaerden E, Vandercam B, Vekemans M, Verhofstede C, Clumeck N, Lepej SZ, Begovac J, Kostrikis L, Demetriades I, Kousiappa I, Demetriou V, Hezka J, Maly M, Machala L, Jørgensen LB, Gerstoft J, Mathiesen L, Pedersen C, Nielsen H, Laursen A, Kvinesdal B, Ristola M, Suni J, Sutinen J, Assoumou L, Castor G, Grude M, Flandre P, Storto A, Kücherer C, Berg T, Braun P, Poggensee G, Däumer M, Eberle J, Heiken H, Kaiser R, Knechten H, Korn K, Müller H, Neifer S, Schmidt B, Walter H, Gunsenheimer-Bartmeyer B, Harrer T, Hatzakis A, Zavitsanou A, Vassilakis A, Lazanas M, Chini M, Lioni A, Sakka V, Kourkounti S, Paparizos V, Antoniadou A, Papadopoulos A, Poulakou G, Katsarolis I, Protopapas K, Chryssos G, Drimis S, Gargalianos P, Xylomenos G, Lourida G, Psichogiou M, Daikos GL, Sipsas NV, Kontos A, Gamaletsou MN, Koratzanis G, Sambatakou H, Mariolis H, Skoutelis A, Papastamopoulos V, Georgiou O, Panagopoulos P, Maltezos E, De Gascun C, Byrne C, Duffy M, Bergin C, Reidy D, Farrell G, Lamber

Abstract

© The Author 2015. Background. Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001. Methods. Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0. Results. The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%-9.5%) in 2008-2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones. Conclusions. Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibi

Published
2016

11. Increase in transmitted resistance to non-nucleoside reverse transcriptase inhibitors among newly diagnosed HIV-1 infections in Europe

Author

Frentz, D. Van de Vijver, D.A.M.C. Abecasis, A.B. Albert, J. Hamouda, O. Jørgensen, L.B. Kücherer, C. Struck, D. Schmit, J.-C. Vercauteren, J. Åsjö, B. Balotta, C. Beshkov, D. Camacho, R.J. Clotet, B. Coughlan, S. Griskevicius, A. Grossman, Z. Horban, A. Kolupajeva, T. Korn, K. Kostrikis, L.G. Liitsola, K. Linka, M. Nielsen, C. Otelea, D. Paraskevis, D. Paredes, R. Poljak, M. Puchhammer-Stöckl, E. Sönnerborg, A. Stanekova, D. Stanojevic, M. Van Wijngaerden, E. Wensing, A.M.J. Boucher, C.A.B. Puchhammer-Stockl, E. Sarcletti, M. Schmied, B. Geit, M. Balluch, G. Vandamme, A.-M. Vercauteren, J. Derdelinckx, I. Sasse, A. Bogaert, M. Ceunen, H. De Roo, A. De Wit, S. Echahidi, F. Fransen, K. Goffard, J.-C. Goubau, P. Goudeseune, E. Yombi, J.-C. Lacor, P. Liesnard, C. Moutschen, M. Pierard, D. Rens, R. Schrooten, Y. Vaira, D. Vandekerckhove, L.P.R. Van den Heuvel, A. Van Der Gucht, B. Van Ranst, M. Vandercam, B. Vekemans, M. Verhofstede, C. Clumeck, N. Van Laethem, K. Demetriades, I. Kousiappa, I. Demetriou, V. Hezka, J. Bruckova, M. Linka, M. Machala, L. Nielsen, C. Jørgensen, L.B. Gerstoft, J. Mathiesen, L. Pedersen, C. Nielsen, H. Laursen, A. Kvinesdal, B. Salminen, M. Ristola, M. Liitsola, K. Suni, J. Sutinen, J. Korn, K. Kücherer, C. Berg, T. Braun, P. Poggensee, G. Däumer, M. Eberle, J. Heiken, H. Kaiser, R. Knechten, H. Müller, H. Neifer, S. Schmidt, B. Walter, H. Gunsenheimer-Bartmeyer, B. Harrer, T. Paraskevis, D. Hatzakis, A. Magiorkinis, E. Hatzitheodorou, E. Haida, C. Zavitsanou, A. Magiorkinis, G. Lazanas, M. Chini, M. Magafas, N. Tsogas, N. Paparizos, V. Kourkounti, S. Antoniadou, A. Papadopoulos, A. Panagopoulos, P. Poulakou, G. Sakka, V. Chryssos, G. Drimis, S. Gargalianos, P. Lelekis, M. Chilomenos, G. Psichogiou, M. Daikos, G.L. Panos, G. Haratsis, G. Kordossis, T. Kontos, A. Koratzanis, G. Theodoridou, M. Mostrou, G. Spoulou, V. Coughlan, S. De Gascun, C. Byrne, C. Duffy, M. Bergin, C. Reidy, D. Farrell, G. Lambert, J. O'Connor, E. Rochford, A. Low, J. Coakely, P. O'Dea, S. Hall, W. Grossman, Z. Levi, I. Chemtob, D. Balotta, C. Riva, C. Mussini, C. Caramma, I. Capetti, A. Colombo, M.C. Rossi, C. Prati, F. Tramuto, F. Vitale, F. Ciccozzi, M. Angarano, G. Rezza, G. Schmit, J.C. Struck, D. Hemmer, R. Arendt, V. Staub, T. Schneider, F. Roman, F. Wensing, A.M.J. Boucher, C.A.B. van Kessel, A. van Bentum, P.H.M. Brinkman, K. op de Coul, E.L. van der Ende, M.E. Hoepelman, I. van Kasteren, M. Juttmann, J. Kuipers, M. Langebeek, N. Richter, C. Santegoets, R. Schrijnders-Gudde, L. Schuurman, R. van de Ven, B.J.M. Åsjö, B. Ormaasen, V. Aavitsland, P. Horban, A. Stanczak, J.J. Stanczak, G.P. Firlag-Burkacka, E. Wiercinska-Drapalo, A. Jablonowska, E. Malolepsza, E. Leszczyszyn-Pynka, M. Szata, W. Camacho, R. Palma, C. Borges, F. Paixão, T. Duque, V. Araújo, F. Jevtovic, D. Salemovic, D. Stanekova, D. Habekova, M. Mokras, M. Truska, P. Poljak, M. Lunar, M. Babic, D. Tomazic, J. Vidmar, L. Vovko, T. Karner, P. Clotet, B. Domingo, P. Galindo, M.J. Miralles, C. del Pozo, M.A. Ribera, E. Iribarren, J.A. Ruiz, L. de la Torre, J. Vidal, F. Garcia, F. Paredes, R. Albert, J. Heidarian, A. Aperia-Peipke, K. Axelsson, M. Mild, M. Karlsson, A. Sönnerborg, A. Thalme, A. Navér, L. Bratt, G. Karlsson, A. Blaxhult, A. Gisslén, M. Svennerholm, B. Bergbrant, I. Björkman, P. Säll, C. Mellgren, Å. Lindholm, A. Kuylenstierna, N. Montelius, R. Azimi, F. Johansson, B. Carlsson, M. Johansson, E. Ljungberg, B. Ekvall, H. Strand, A. Mäkitalo, S. öberg, S. Holmblad, P. Höfer, M. Holmberg, H. Josefson, P. Ryding, U. on behalf of the SPREAD Programme

Abstract

Background: One out of ten newly diagnosed patients in Europe was infected with a virus carrying a drug resistant mutation. We analysed the patterns over time for transmitted drug resistance mutations (TDRM) using data from the European Spread program.Methods: Clinical, epidemiological and virological data from 4317 patients newly diagnosed with HIV-1 infection between 2002 and 2007 were analysed. Patients were enrolled using a pre-defined sampling strategy.Results: The overall prevalence of TDRM in this period was 8.9% (95% CI: 8.1-9.8). Interestingly, significant changes over time in TDRM caused by the different drug classes were found. Whereas nucleoside resistance mutations remained constant at 5%, a significant decline in protease inhibitors resistance mutations was observed, from 3.9% in 2002 to 1.6% in 2007 (p = 0.001). In contrast, resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) doubled from 2.0% in 2002 to 4.1% in 2007 (p = 0.004) with 58% of viral strains carrying a K103N mutation. Phylogenetic analysis showed that these temporal changes could not be explained by large clusters of TDRM.Conclusion: During the years 2002 to 2007 transmitted resistance to NNRTI has doubled to 4% in Europe. The frequent use of NNRTI in first-line regimens and the clinical impact of NNRTI mutations warrants continued monitoring. © 2014 Frentz et al.; licensee BioMed Central Ltd.

Published
2014

12. Cellular HIV-1 DNA levels in drug sensitive strains are equivalent to those in drug resistant strains in newly-diagnosed patients in Europe

Author

Demetriou, V.L. (Victoria), Vijver, D.A.M.C. (David) van de, Kousiappa, I. (Ioanna), Balotta, C. (Claudia), Clotet, B. (Bonaventura), Grossman, Z. (Zehava), Jørgensen, L.B. (Louise), Lepej, S.Z. (Snjezana), Levy, I. (Itzchak), Nielsen, C. (Claus), Paraskevis, D. (Dimitrios), Poljak, M. (Mario), Roman, F. (Francois), Ruiz, L. (Lidia), Schmidt, J.C., Vandamme, A.M. (Anne Mieke), Laethem, K. (Kristel), Vercauteren, J. (Jurgen), Kostrikis, L.G. (Leondios), Demetriou, V.L. (Victoria), Vijver, D.A.M.C. (David) van de, Kousiappa, I. (Ioanna), Balotta, C. (Claudia), Clotet, B. (Bonaventura), Grossman, Z. (Zehava), Jørgensen, L.B. (Louise), Lepej, S.Z. (Snjezana), Levy, I. (Itzchak), Nielsen, C. (Claus), Paraskevis, D. (Dimitrios), Poljak, M. (Mario), Roman, F. (Francois), Ruiz, L. (Lidia), Schmidt, J.C., Vandamme, A.M. (Anne Mieke), Laethem, K. (Kristel), Vercauteren, J. (Jurgen), and Kostrikis, L.G. (Leondios)

Abstract

Background HIV-1 genotypic drug resistance is an important threat to the success of antiretroviral therapy and transmitted resistance has reached 9% prevalence in Europe. Studies have demonstrated that HIV-1 DNA load in peripheral blood mononuclear cells (PBMC) have a predictive value for disease progression, independently of CD4 counts and plasma viral load. Methodology/Principal Findings Molecular-beacon-based real-time PCR was used to measure HIV-1 second template switch (STS) DNA in PBMC in newly-diagnosed HIV-1 patients across Europe. These patients were representative for the HIV-1 epidemic in the participating countries and were carrying either drug-resistant or sensitive viral strains. The assay design was improved from a previous version to specifically detect M-group HIV-1 and human CCR5 alleles. The findings resulted in a median of 3.32 log10HIV-1copies/106PBMC and demonstrated for the first time no correlation between cellular HIV-1 DNA load and transmitted drug-resistance. A weak association between cellular HIV-1 DNA levels with plasma viral RNA load and CD4+T-cell counts was also reconfirmed. Co-receptor tropism for 91% of samples, whether or not they conferred resistance, was CCR5. A comparison of pol sequences derived from RNA and DNA, resulted in a high similarity between the two. Conclusions/Significance An improved molecular-beacon-based real-time PCR assay is reported for the measurement of HIV-1 DNA in PBMC and has investigated the association between cellular HIV-1 DNA levels and transmitted resistance to antiretroviral therapy in newly-diagnosed patients from across Europe. The findings show no correlation between these two parameters, suggesting that transmitted resistance does not impact disease progression in HIV-1 infected individuals. The CCR5 co-receptor tropism predominance implies that both resistant and non-resistant strains behave similarly in early infection. Furthe

Published
2010
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13. Cellular HIV-1 DNA Levels in Drug Sensitive Strains Are Equivalent to Those in Drug Resistant Strains in Newly-Diagnosed Patients in Europe

Author

Demetriou, VL, van de Vijver, David, Kousiappa, I, Balotta, C, Clotet, B, Grossman, Z, Jorgensen, LB, Lepej, SZ, Levy, I, Nielsen, C, Paraskevis, D, Poljak, M, Roman, F, Ruiz, L, Schmidt, JC, Vandamme, AM, Van Laethem, K, Vercauteren, J, Kostrikis, LG, Demetriou, VL, van de Vijver, David, Kousiappa, I, Balotta, C, Clotet, B, Grossman, Z, Jorgensen, LB, Lepej, SZ, Levy, I, Nielsen, C, Paraskevis, D, Poljak, M, Roman, F, Ruiz, L, Schmidt, JC, Vandamme, AM, Van Laethem, K, Vercauteren, J, and Kostrikis, LG

Abstract

Background: HIV-1 genotypic drug resistance is an important threat to the success of antiretroviral therapy and transmitted resistance has reached 9% prevalence in Europe. Studies have demonstrated that HIV-1 DNA load in peripheral blood mononuclear cells (PBMC) have a predictive value for disease progression, independently of CD4 counts and plasma viral load. Methodology/Principal Findings: Molecular-beacon-based real-time PCR was used to measure HIV-1 second template switch (STS) DNA in PBMC in newly-diagnosed HIV-1 patients across Europe. These patients were representative for the HIV-1 epidemic in the participating countries and were carrying either drug-resistant or sensitive viral strains. The assay design was improved from a previous version to specifically detect M-group HIV-1 and human CCR5 alleles. The findings resulted in a median of 3.32 log(10) HIV-1 copies/10(6) PBMC and demonstrated for the first time no correlation between cellular HIV-1 DNA load and transmitted drug-resistance. A weak association between cellular HIV-1 DNA levels with plasma viral RNA load and CD4(+) T-cell counts was also reconfirmed. Co-receptor tropism for 91% of samples, whether or not they conferred resistance, was CCR5. A comparison of pol sequences derived from RNA and DNA, resulted in a high similarity between the two. Conclusions/Significance: An improved molecular-beacon-based real-time PCR assay is reported for the measurement of HIV-1 DNA in PBMC and has investigated the association between cellular HIV-1 DNA levels and transmitted resistance to antiretroviral therapy in newly-diagnosed patients from across Europe. The findings show no correlation between these two parameters, suggesting that transmitted resistance does not impact disease progression in HIV-1 infected individuals. The CCR5 co-receptor tropism predominance implies that both resistant and non-resistant strains behave similarly in early infection. Furthermore, a correlation found between RNA-and DNA-derived

Published
2010

15. Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants

Author

Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika Verena, Brünger, Tobias, Hedrich, Ulrike B. S., Augustijn, Paul B., Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J., Bruria, Ben Zeev, Doyle, Michael G., Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, Kunz, Wolfram S., Lerche, Holger, Licchetta, Laura, Lohmann, Ebba, Minardi, Raffaella, McDonald, Marie, Montgomery, Sarah, Mulahasanovic, Lejla, Oegema, Renske, Ortal, Barel, Papacostas, Savvas S., Ragona, Francesca, Granata, Tiziana, Reif, Phillip S., Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A., Vetro, Annalisa, Zahnert, Felix, Goldberg, Ethan M., Zara, Federico, Lal, Dennis, May, Patrick, Muhle, Hiltrud, Helbig, Ingo, Weber, Yvonne, Schwarz N., Seiffert S., Pendziwiat M., Rademacher A.V., Brunger T., Hedrich U.B.S., Augustijn P.B., Baier H., Bayat A., Bisulli F., Buono R.J., Bruria B.Z., Doyle M.G., Guerrini R., Heimer G., Iacomino M., Kearney H., Klein K.M., Kousiappa I., Kunz W.S., Lerche H., Licchetta L., Lohmann E., Minardi R., McDonald M., Montgomery S., Mulahasanovic L., Oegema R., Ortal B., Papacostas S.S., Ragona F., Granata T., Reif P.S., Rosenow F., Rothschild A., Scudieri P., Striano P., Tinuper P., Tanteles G.A., Vetro A., Zahnert F., Goldberg E.M., Zara F., Lal D., May P., Muhle H., Helbig I., and Weber Y.

Subjects
Phenotype, Epilepsy, Shaw Potassium Channel, Epilepsy, Generalized, Seizure, Whole Exome Sequencing, Human
Abstract

Neurology : official journal of the American Academy of Neurology 98(20), e2046-e2059 (2022). doi:10.1212/WNL.0000000000200660, Published by Ovid, [S.l.]

Published
2022
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16. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author

Joshua E. Motelow, Gundula Povysil, Ryan S. Dhindsa, Kate E. Stanley, Andrew S. Al- len, Yen-Chen Anne Feng, Daniel P. Howrigan, Liam E. Abbott, Ka- therine Tashman, Felecia Cerrato, Caroline Cusick, Tarjinder Singh, Henrike Heyne, Andrea E. Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Namrata Gupta, Benjamin M. Neale, Gianpiero L. Cavalleri, Patrick Cossette, Chris Cotsapas, Peter De Jonghe, Tracy Dixon-Salazar, Renzo Guerrini, Hakon Hakonarson, Erin L. Heinzen, Ingo Helbig, Patrick Kwan, Anthony G. Marson, Slave ? Petrovski, Sitharthan Kamalakaran, Sanjay M. Sisodiya, Randy Stewart, Sarah Weckhuysen, Chantal Depondt, Dennis J. Dlugos, Ingrid E. Scheffer, Pasquale Striano, Catharine Freyer, Roland Krause, Patrick May, Kevin McKenna, Brigid M. Regan, Caitlin A. Bennett, Costin Leu, Stephanie L. Leech, Terence J. O'Brien, Marian Todaro, Hannah Stamberger, Danielle M. Andrade, Quratulain Zulfiqar Ali, Tara R. Sadoway, Heinz Krestel, Andre ? Schaller, Savvas S. Papacostas, Ioanna Kou- siappa, George A. Tanteles, Yiolanda Christou, Katalin Sterbova ?, Marke ? ta Vlckova ?, Lucie Sedlackova, Petra Lassuthova ?, Karl Martin Klein, Felix Rosenow, Philipp S. Reif, Susanne Knake, Bernd A. Neubauer, Friedrich Zimprich, Martha Feucht, Eva M. Reinthaler, Wolfram S. Kunz, Ga ?bor Zsurka, Rainer Surges, Tobias Baumgart- ner, Randi von Wrede, Manuela Pendziwiat, Hiltrud Muhle, An- nika Rademacher, Andreas van Baalen, Sarah von Spiczak, Ulrich Stephani, Zaid Afawi, Amos D. Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Mu ?ller-Schlu ?ter, Gerhard Kluger, Martin Ha ?usler, Ilan Blatt, Johannes R. Lemke, Ilona Krey, Yvonne G. Weber, Stefan Wolking, Felicitas Becker, Stephan Lauxmann, Christian Boßelmann, Josua Kegele, Christian Hengs- bach, Sarah Rau, Bernhard J. Steinhoff, Andreas Schulze-Bonhage, IngoBorggra ?fe, ChristophJ.Schankin, SusanneSchubert-Bast, Herbert Schreiber, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Markus Wolff, Dieter Dennig, Rene Madeleyn, Reetta Ka ?lvia ?inen, Anni Saarela, Oskari Timonen, Tarja Linnankivi, Anna-Elina Lehesjoki, Sylvain Rheims, Gaetan Lesca, Philippe Ryvlin, Louis Maillard, Luc Valton, Philippe Derambure, Fabrice Bartolomei, Edouard Hirsch, Ve ?ronique Michel, Francine Chas- soux, Mark I. Rees, Seo-Kyung Chung, William O. Pickrell, Robert Powell, Mark D. Baker, Beata Fonferko-Shadrach, Charlotte Law- thom, Joseph Anderson, Natascha Schneider, Simona Balestrini, Sara Zagaglia, Vera Braatz, Michael R. Johnson, Pauls Auce, Graeme J. Sills, Larry W. Baum, Pak C. Sham, Stacey S. Cherny, Colin H.T. Lui, Norman Delanty, Colin P. Doherty, Arif Shukralla, Hany El-Naggar, Peter Widdess-Walsh, Nina Barisic, Laura 12 The American Journal of Human Genetics 108, 1-18, June 3, 2021 Please cite this article in press as: Epi25 Collaborative, Sub-genic intolerance, ClinVar, the epilepsies: A whole-exome sequencing study of 29, 165 individuals, The American Journal of Human Genetics (2021), https://doi.org/10.1016/j.ajhg.2021.04.009 Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Francesca Ragona, Federico Zara, Michele Iacomino, An- tonella Riva, Francesca Madia, Maria Stella Vari, Vincenzo Salpie- tro, Marcello Scala, Maria Margherita Mancardi, Lino Nobili, Elisa- betta Amadori, Thea Giacomini, Francesca Bisulli, Tommaso Pippucci, Laura Licchetta, Raffaella Minardi, Paolo Tinuper, Lor- enzo Muccioli, Barbara Mostacci, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carmen Barba, Shinichi Hirose, At- sushi Ishii, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Ahmad Beydoun, Wassim Nasreddine, Nathalie Khoueiry Zgheib, Birute Tumiene, Algirdas Utkus, Lynette G. Sadleir, Chontelle King, S. Hande Caglayan, Mutluay Arslan, Zuhal Yap?c?, P?nar To- paloglu, Bulent Kara, Uluc Yis, Dilsad Turkdogan, Asl? Gun- dogdu-Eken, Nerses Bebek, Meng-Han Tsai, Chen-Jui Ho, Chih- Hsiang Lin, Kuang-Lin Lin, I-Jun Chou, Annapurna Poduri, Beth R. Shiedley, Catherine Shain, Jeffrey L. Noebels, Alicia Goldman, Robyn M. Busch, Lara Jehi, Imad M. Najm, Lisa Ferguson, Jean Khoury, Tracy A. Glauser, Peggy O. Clark, Russell J. Buono, Thomas N. Ferraro, Michael R. Sperling, Warren Lo, Michael Privitera, Jac- queline A. French, Steven Schachter, Ruben I. Kuzniecky, Orrin Devinsky, Manu Hegde, David A. Greenberg, Colin A. Ellis, Ethan Goldberg, Katherine L. Helbig, Mahgenn Cosico, Priya Vaidis- waran, Eryn Fitch, Samuel F. Berkovic, Holger Lerche, Daniel H. Lowenstein, David B. Goldstein., Motelow J.E., Povysil G., Dhindsa R.S., Stanley K.E., Allen A.S., Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Cusick C., Singh T., Heyne H., Byrnes A.E., Churchhouse C., Watts N., Solomonson M., Lal D., Gupta N., Neale B.M., Cavalleri G.L., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E.L., Helbig I., Kwan P., Marson A.G., Petrovski S., Kamalakaran S., Sisodiya S.M., Stewart R., Weckhuysen S., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B.M., Bennett C.A., Leu C., Leech S.L., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Ali Q.Z., Sadoway T.R., Krestel H., Schaller A., Papacostas S.S., Kousiappa I., Tanteles G.A., Christou Y., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Neubauer B.A., Zimprich F., Feucht M., Reinthaler E.M., Kunz W.S., Zsurka G., Surges R., Baumgartner T., von Wrede R., Pendziwiat M., Muhle H., Rademacher A., van Baalen A., von Spiczak S., Stephani U., Afawi Z., Korczyn A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Lauxmann S., Bosselmann C., Kegele J., Hengsbach C., Rau S., Steinhoff B.J., Schulze-Bonhage A., Borggrafe I., Schankin C.J., Schubert-Bast S., Schreiber H., Mayer T., Korinthenberg R., Brockmann K., Wolff M., Dennig D., Madeleyn R., Kalviainen R., Saarela A., Timonen O., Linnankivi T., Lehesjoki A.-E., Rheims S., Lesca G., Ryvlin P., Maillard L., Valton L., Derambure P., Bartolomei F., Hirsch E., Michel V., Chassoux F., Rees M.I., Chung S.-K., Pickrell W.O., Powell R., Baker M.D., Fonferko-Shadrach B., Lawthom C., Anderson J., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Delanty N., Doherty C.P., Shukralla A., El-Naggar H., Widdess-Walsh P., Barisic N., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Ragona F., Zara F., Iacomino M., Riva A., Madia F., Vari M.S., Salpietro V., Scala M., Mancardi M.M., Nobili L., Amadori E., Giacomini T., Bisulli F., Pippucci T., Licchetta L., Minardi R., Tinuper P., Muccioli L., Mostacci B., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Barba C., Hirose S., Ishii A., Suzuki T., Inoue Y., Yamakawa K., Beydoun A., Nasreddine W., Khoueiry Zgheib N., Tumiene B., Utkus A., Sadleir L.G., King C., Caglayan S.H., Arslan M., Yapici Z., Topaloglu P., Kara B., Yis U., Turkdogan D., Gundogdu-Eken A., Bebek N., Tsai M.-H., Ho C.-J., Lin C.-H., Lin K.-L., Chou I.-J., Poduri A., Shiedley B.R., Shain C., Noebels J.L., Goldman A., Busch R.M., Jehi L., Najm I.M., Ferguson L., Khoury J., Glauser T.A., Clark P.O., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Greenberg D.A., Ellis C.A., Goldberg E., Helbig K.L., Cosico M., Vaidiswaran P., Fitch E., Berkovic S.F., Lerche H., Lowenstein D.H., Goldstein D.B., Epi25 Collaborative, Institut de Neurosciences des Systèmes (INS), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, focal epilepsy, Whole Exome Sequencing, Cohort Studies, Epilepsy, 0302 clinical medicine, Genetic Marker, Missense mutation, Exome, whole-exome sequencing, generalized epilepsy, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Exome sequencing, seizures, Genetics, ClinVar, Phenotype, epileptic encephalopathy, Epi25, intolerance, Case-Control Studie, Human, Genetic Markers, seizure, Disease Association, Biology, Article, 03 medical and health sciences, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Generalized epilepsy, Gene, Louvain, [SCCO.NEUR]Cognitive science/Neuroscience, Correction, Genetic Variation, medicine.disease, epilepsy, Human genetics, 030104 developmental biology, Case-Control Studies, Human medicine, Cohort Studie, Genetic generalized epilepsy, 030217 neurology & neurosurgery
Abstract

Summary Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.

Published
2021
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17. Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.

Author

Chen S, Abou-Khalil BW, Afawi Z, Ali QZ, Amadori E, Anderson A, Anderson J, Andrade DM, Annesi G, Arslan M, Auce P, Bahlo M, Baker MD, Balagura G, Balestrini S, Banks E, Barba C, Barboza K, Bartolomei F, Bass N, Baum LW, Baumgartner TH, Baykan B, Bebek N, Becker F, Bennett CA, Beydoun A, Bianchini C, Bisulli F, Blackwood D, Blatt I, Borggräfe I, Bosselmann C, Braatz V, Brand H, Brockmann K, Buono RJ, Busch RM, Caglayan SH, Canafoglia L, Canavati C, Castellotti B, Cavalleri GL, Cerrato F, Chassoux F, Cherian C, Cherny SS, Cheung CL, Chou IJ, Chung SK, Churchhouse C, Ciullo V, Clark PO, Cole AJ, Cosico M, Cossette P, Cotsapas C, Cusick C, Daly MJ, Davis LK, Jonghe P, Delanty N, Dennig D, Depondt C, Derambure P, Devinsky O, Di Vito L, Dickerson F, Dlugos DJ, Doccini V, Doherty CP, El-Naggar H, Ellis CA, Epstein L, Evans M, Faucon A, Feng YA, Ferguson L, Ferraro TN, Da Silva IF, Ferri L, Feucht M, Fields MC, Fitzgerald M, Fonferko-Shadrach B, Fortunato F, Franceschetti S, French JA, Freri E, Fu JM, Gabriel S, Gagliardi M, Gambardella A, Gauthier L, Giangregorio T, Gili T, Glauser TA, Goldberg E, Goldman A, Goldstein DB, Granata T, Grant R, Greenberg DA, Guerrini R, Gundogdu-Eken A, Gupta N, Haas K, Hakonarson H, Haryanyan G, Häusler M, Hegde M, Heinzen EL, Helbig I, Hengsbach C, Heyne H, Hirose S, Hirsch E, Ho CJ, Hoeper O, Howrigan DP, Hucks D, Hung PC, Iacomino M, Inoue Y, Inuzuka LM, Ishii A, Jehi L, Johnson MR, Johnstone M, Kälviäinen R, Kanaan M, Kara B, Kariuki SM, Kegele J, Kesim Y, Khoueiry-Zgheib N, Khoury J, King C, Klein KM, Kluger G, Knake S, Kok F, Korczyn AD, Korinthenberg R, Koupparis A, Kousiappa I, Krause R, Krenn M, Krestel H, Krey I, Kunz WS, Kurlemann G, Kuzniecky RI, Kwan P, La Vega-Talbott M, Labate A, Lacey A, Lal D, Laššuthová P, Lauxmann S, Lawthom C, Leech SL, Lehesjoki AE, Lemke JR, Lerche H, Lesca G, Leu C, Lewin N, Lewis-Smith D, Li GH, Liao C, Licchetta L, Lin CH, Lin KL, Linnankivi T, Lo W, Lowenstein DH, Lowther C, Lubbers L, Lui CHT, Macedo-Souza LI, Madeleyn R, Madia F, Magri S, Maillard L, Marcuse L, Marques P, Marson AG, Matthews AG, May P, Mayer T, McArdle W, McCarroll SM, McGoldrick P, McGraw CM, McIntosh A, McQuillan A, Meador KJ, Mei D, Michel V, Millichap JJ, Minardi R, Montomoli M, Mostacci B, Muccioli L, Muhle H, Müller-Schlüter K, Najm IM, Nasreddine W, Neaves S, Neubauer BA, Newton CRJC, Noebels JL, Northstone K, Novod S, O'Brien TJ, Owusu-Agyei S, Özkara Ç, Palotie A, Papacostas SS, Parrini E, Pato C, Pato M, Pendziwiat M, Pennell PB, Petrovski S, Pickrell WO, Pinsky R, Pinto D, Pippucci T, Piras F, Piras F, Poduri A, Pondrelli F, Posthuma D, Powell RHW, Privitera M, Rademacher A, Ragona F, Ramirez-Hamouz B, Rau S, Raynes HR, Rees MI, Regan BM, Reif A, Reinthaler E, Rheims S, Ring SM, Riva A, Rojas E, Rosenow F, Ryvlin P, Saarela A, Sadleir LG, Salman B, Salmon A, Salpietro V, Sammarra I, Scala M, Schachter S, Schaller A, Schankin CJ, Scheffer IE, Schneider N, Schubert-Bast S, Schulze-Bonhage A, Scudieri P, Sedláčková L, Shain C, Sham PC, Shiedley BR, Siena SA, Sills GJ, Sisodiya SM, Smoller JW, Solomonson M, Spalletta G, Sparks KR, Sperling MR, Stamberger H, Steinhoff BJ, Stephani U, Štěrbová K, Stewart WC, Stipa C, Striano P, Strzelczyk A, Surges R, Suzuki T, Talarico M, Talkowski ME, Taneja RS, Tanteles GA, Timonen O, Timpson NJ, Tinuper P, Todaro M, Topaloglu P, Tsai MH, Tumiene B, Turkdogan D, Uğur-İşeri S, Utkus A, Vaidiswaran P, Valton L, van Baalen A, Vari MS, Vetro A, Vlčková M, von Brauchitsch S, von Spiczak S, Wagner RG, Watts N, Weber YG, Weckhuysen S, Widdess-Walsh P, Wiebe S, Wolf SM, Wolff M, Wolking S, Wong I, von Wrede R, Wu D, Yamakawa K, Yapıcı Z, Yis U, Yolken R, Yücesan E, Zagaglia S, Zahnert F, Zara F, Zimprich F, Zizovic M, Zsurka G, Neale BM, and Berkovic SF

Abstract

Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies, generalized and focal epilepsies, while most other gene discoveries are subtype-specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single nucleotide/short indel-, copy number-, and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies., Competing Interests: Competing Interests B.M.N is a member of the scientific advisory board at Deep Genomics and Neumora. No other authors have competing interests to declare

Published
2024
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18. FUS-mediated blood-brain barrier disruption for delivering anti-Aβ antibodies in 5XFAD Alzheimer's disease mice.

Author

Antoniou A, Stavrou M, Evripidou N, Georgiou E, Kousiappa I, Koupparis A, Papacostas SS, Kleopa KA, and Damianou C

Subjects
Animals, Mice, Microbubbles, Brain diagnostic imaging, Brain metabolism, Drug Delivery Systems methods, Sonication methods, Antibodies, Blood-Brain Barrier, Alzheimer Disease, Amyloid beta-Peptides metabolism, Amyloid beta-Peptides immunology, Disease Models, Animal, Mice, Transgenic
Abstract

Purpose: Amyloid-β (Aβ) peptides, the main component of amyloid plaques found in the Alzheimer's disease (AD) brain, are implicated in its pathogenesis, and are considered a key target in AD therapeutics. We herein propose a reliable strategy for non-invasively delivering a specific anti-Aβ antibody in a mouse model of AD by microbubbles-enhanced Focused Ultrasound (FUS)-mediated Blood-brain barrier disruption (BBBD), using a simple single stage MR-compatible positioning device., Methods: The initial experimental work involved wild-type mice and was devoted to selecting the sonication protocol for efficient and safe BBBD. Pulsed FUS was applied using a single-element FUS transducer of 1 MHz (80 mm radius of curvature and 50 mm diameter). The success and extent of BBBD were assessed by Evans Blue extravasation and brain damage by hematoxylin and eosin staining. 5XFAD mice were divided into different subgroups; control (n = 1), FUS + MBs alone (n = 5), antibody alone (n = 5), and FUS + antibody combined (n = 10). The changes in antibody deposition among groups were determined by immunohistochemistry., Results: It was confirmed that the antibody could not normally enter the brain parenchyma. A single treatment with MBs-enhanced pulsed FUS using the optimized protocol (1 MHz, 0.5 MPa in-situ pressure, 10 ms bursts, 1% duty factor, 100 s duration) transiently disrupted the BBB allowing for non-invasive antibody delivery to amyloid plaques within the sonicated brain regions. This was consistently reproduced in ten mice., Conclusion: These preliminary findings should be confirmed by longer-term studies examining the antibody effects on plaque clearance and cognitive benefit to hold promise for developing disease-modifying anti-Aβ therapeutics for clinical use., (© 2023. The Author(s).)

Published
2024
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19. Glial Gap Junction Pathology in the Spinal Cord of the 5xFAD Mouse Model of Early-Onset Alzheimer's Disease.

Author

Pechlivanidou M, Kousiappa I, Angeli S, Sargiannidou I, Koupparis AM, Papacostas SS, and Kleopa KA

Subjects
Mice, Animals, Gap Junctions metabolism, Connexins metabolism, Neuroglia metabolism, Spinal Cord metabolism, Mice, Transgenic, Disease Models, Animal, Alzheimer Disease metabolism
Abstract

Gap junctions (GJs) are specialized transmembrane channels assembled by two hemi-channels of six connexin (Cx) proteins that facilitate neuroglial crosstalk in the central nervous system (CNS). Previous studies confirmed the crucial role of glial GJs in neurodegenerative disorders with dementia or motor dysfunction including Alzheimer's disease (AD). The aim of this study was to examine the alterations in astrocyte and related oligodendrocyte GJs in association with Aβ plaques in the spinal cord of the 5xFAD mouse model of AD. Our analysis revealed abundant Aβ plaque deposition, activated microglia, and astrogliosis in 12-month-old (12M) 5xFAD mice, with significant impairment of motor performance starting from 3-months (3M) of age. Additionally, 12M 5xFAD mice displayed increased immunoreactivity of astroglial Cx43 and Cx30 surrounding Aβ plaques and higher protein levels, indicating upregulated astrocyte-to-astrocyte GJ connectivity. In addition, they demonstrated increased numbers of mature CC1-positive and precursor oligodendrocytes (OPCs) with higher immunoreactivity of Cx47-positive GJs in individual cells. Moreover, total Cx47 protein levels were significantly elevated in 12M 5xFAD, reflecting increased oligodendrocyte-to-oligodendrocyte Cx47-Cx47 GJ connectivity. In contrast, we observed a marked reduction in Cx32 protein levels in 12M 5xFAD spinal cords compared with controls, while qRT-PCR analysis revealed a significant upregulation in Cx32 mRNA levels. Finally, myelin deficits were found focally in the areas occupied by Aβ plaques, whereas axons themselves remained preserved. Overall, our data provide novel insights into the altered glial GJ expression in the spinal cord of the 5xFAD model of AD and the implicated role of GJ pathology in neurodegeneration. Further investigation to understand the functional consequences of these extensive alterations in oligodendrocyte-astrocyte (O/A) GJ connectivity is warranted.

Published
2022
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20. Pathogenic and Low-Frequency Variants in Children With Central Precocious Puberty.

Author

Neocleous V, Fanis P, Toumba M, Gorka B, Kousiappa I, Tanteles GA, Iasonides M, Nicolaides NC, Christou YP, Michailidou K, Nicolaou S, Papacostas SS, Christoforidis A, Kyriakou A, Vlachakis D, Skordis N, and Phylactou LA

Subjects
Brain Diseases epidemiology, Brain Diseases genetics, Calcium-Binding Proteins genetics, Child, Child, Preschool, Cohort Studies, Cyprus epidemiology, DNA Mutational Analysis, Female, Gene Frequency, High-Throughput Nucleotide Sequencing, Humans, Kisspeptins genetics, Male, Membrane Proteins genetics, Mutation, Puberty, Precocious epidemiology, Receptors, Kisspeptin-1 genetics, Ubiquitin-Protein Ligases genetics, Exome Sequencing, Puberty, Precocious genetics
Abstract

Background: Central precocious puberty (CPP) due to premature activation of GnRH secretion results in early epiphyseal fusion and to a significant compromise in the achieved final adult height. Currently, few genetic determinants of children with CPP have been described. In this translational study, rare sequence variants in MKRN3 , DLK1 , KISS1 , and KISS1R genes were investigated in patients with CPP., Methods: Fifty-four index girls and two index boys with CPP were first tested by Sanger sequencing for the MKRN3 gene. All children found negative ( n = 44) for the MKRN3 gene were further investigated by whole exome sequencing (WES). In the latter analysis, the status of variants in genes known to be related with pubertal timing was compared with an in-house Cypriot control cohort (n = 43). The identified rare variants were initially examined by in silico computational algorithms and confirmed by Sanger sequencing. Additionally, a genetic network for the MKRN3 gene, mimicking a holistic regulatory depiction of the crosstalk between MKRN3 and other genes was designed., Results: Three previously described pathogenic MKRN3 variants located in the coding region of the gene were identified in 12 index girls with CPP. The most prevalent pathogenic MKRN3 variant p.Gly312Asp was exclusively found among the Cypriot CPP cohort, indicating a founder effect phenomenon. Seven other CPP girls harbored rare likely pathogenic upstream variants in the MKRN3. Among the 44 CPP patients submitted to WES, nine rare DLK1 variants were identified in 11 girls, two rare KISS1 variants in six girls, and two rare MAGEL2 variants in five girls. Interestingly, the frequent variant rs10407968 (p.Gly8Ter) of the KISS1R gene appeared to be less frequent in the cohort of patients with CPP., Conclusion: The results of the present study confirm the importance of the MKRN3-imprinted gene in genetics of CPP and its key role in pubertal timing. Overall, the results of the present study have emphasized the importance of an approach that aligns genetics and clinical aspects, which is necessary for the management and treatment of CPP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Neocleous, Fanis, Toumba, Gorka, Kousiappa, Tanteles, Iasonides, Nicolaides, Christou, Michailidou, Nicolaou, Papacostas, Christoforidis, Kyriakou, Vlachakis, Skordis and Phylactou.)

Published
2021
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21. Altered Expression of Glial Gap Junction Proteins Cx43, Cx30, and Cx47 in the 5XFAD Model of Alzheimer's Disease.

Author

Angeli S, Kousiappa I, Stavrou M, Sargiannidou I, Georgiou E, Papacostas SS, and Kleopa KA

Abstract

Glial gap junction proteins, called connexins (Cxs), form gap junctions in the central nervous system (CNS) to allow the bidirectional cytosolic exchange of molecules between adjacent cells. Their involvement in inheritable diseases and the use of experimental animal models that closely mimic such diseases revealed the critical role of glial GJs in myelination and homeostasis. Cxs are also implicated in acquired demyelinating disorders, such as Multiple Sclerosis (MS) and Alzheimer's disease (AD). Animal and human studies have revealed a role of the astrocytic Cx43 in the progression of AD but the role of Cx47, which is the main partner of Cx43 in the astrocyte-oligodendrocyte GJs is still unknown. The aim of this study was to investigate the astrocytic connexins, Cx43 and Cx30 in relation to oligodendrocytic Cx47 in the cortex and thalamus of the 5XFAD mouse model of AD. The model was characterized by increased Aβ deposition, gliosis, neuronal loss, and memory impairment. Compared to wild-type mice, Cx43 and Cx30 showed increased immunoreactivity in older 5XFAD mice, reflecting astrogliosis, while Cx47 immunoreactivity was reduced. Moreover, Cx47 GJ plaques showed reduced colocalization with Cx43 plaques. Oligodendrocyte precursor cells (OPCs) and mature oligodendrocyte populations were also depleted, and myelin deficits were observed. Our findings indicate reduced astrocyte-oligodendrocyte gap junction connectivity and possibly a shift in Cx43 expression toward astrocyte-astrocyte gap junctions and/or hemichannels, that could impair oligodendrocyte homeostasis and myelination. However, other factors, such as Aβ toxicity, could directly affect oligodendrocyte survival in AD. Our study provides evidence that Cxs might have implications in the progression of AD, although the role of oligodendrocyte Cxs in AD requires further investigation., (Copyright © 2020 Angeli, Kousiappa, Stavrou, Sargiannidou, Georgiou, Papacostas and Kleopa.)

Published
2020
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22. Neurophysiological and Genetic Findings in Patients With Juvenile Myoclonic Epilepsy.

Author

Stefani S, Kousiappa I, Nicolaou N, Papathanasiou ES, Oulas A, Fanis P, Neocleous V, Phylactou LA, Spyrou GM, and Papacostas SS

Abstract

Objective: Transcranial magnetic stimulation (TMS), a non-invasive procedure, stimulates the cortex evaluating the central motor pathways. The response is called motor evoked potential (MEP). Polyphasia results when the response crosses the baseline more than twice (zero crossing). Recent research shows MEP polyphasia in patients with generalized genetic epilepsy (GGE) and their first-degree relatives compared with controls. Juvenile Myoclonic Epilepsy (JME), a GGE type, is not well studied regarding polyphasia. In our study, we assessed polyphasia appearance probability with TMS in JME patients, their healthy first-degree relatives and controls. Two genetic approaches were applied to uncover genetic association with polyphasia., Methods: 20 JME patients, 23 first-degree relatives and 30 controls underwent TMS, obtaining 10-15 MEPs per participant. We evaluated MEP mean number of phases, proportion of MEP trials displaying polyphasia for each subject and variability between groups. Participants underwent whole exome sequencing (WES) via trio-based analysis and two-case scenario. Extensive bioinformatics analysis was applied., Results: We identified increased polyphasia in patients (85%) and relatives (70%) compared to controls (47%) and significantly higher mean number of zero crossings (i.e., occurrence of phases) (patients 1.49, relatives 1.46, controls 1.22; p < 0.05). Trio-based analysis revealed a candidate polymorphism, p.Glu270del,in SYT14 (Synaptotagmin 14) , in JME patients and their relatives presenting polyphasia. Sanger sequencing analysis in remaining participants showed no significant association. In two-case scenario, a machine learning approach was applied in variants identified from odds ratio analysis and risk prediction scores were obtained for polyphasia. The results revealed 61 variants of which none was associated with polyphasia. Risk prediction scores indeed showed lower probability for non-polyphasic subjects on having polyphasia and higher probability for polyphasic subjects on having polyphasia., Conclusion: Polyphasia was present in JME patients and relatives in contrast to controls. Although no known clinical symptoms are linked to polyphasia this neurophysiological phenomenon is likely due to common cerebral electrophysiological abnormality. We did not discover direct association between genetic variants obtained and polyphasia. It is likely these genetic traits alone cannot provoke polyphasia, however, this predisposition combined with disturbed brain-electrical activity and tendency to generate seizures may increase the risk of developing polyphasia, mainly in patients and relatives., (Copyright © 2020 Stefani, Kousiappa, Nicolaou, Papathanasiou, Oulas, Fanis, Neocleous, Phylactou, Spyrou and Papacostas.)

Published
2020
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23. C5aR agonist enhances phagocytosis of fibrillar and non-fibrillar Aβ amyloid and preserves memory in a mouse model of familial Alzheimer's disease.

Author

Panayiotou E, Fella E, Andreou S, Papacharalambous R, Gerasimou P, Costeas P, Angeli S, Kousiappa I, Papacostas S, and Kyriakides T

Subjects
Alzheimer Disease genetics, Amyloid metabolism, Animals, Brain drug effects, Brain metabolism, Disease Models, Animal, Mice, Mice, Transgenic, Neurons drug effects, Neurons metabolism, Alzheimer Disease metabolism, Amyloid drug effects, Amyloid beta-Peptides metabolism, Memory drug effects, Oligopeptides pharmacology, Phagocytosis drug effects
Abstract

According to the amyloid hypothesis of Alzheimer's disease (AD) the deposition of prefibrillar and fibrillar Aβ peptide sets off the pathogenic cascades of neuroinflammation and neurodegeneration that lead to synaptic and neuronal loss resulting in cognitive decline. Various approaches to reduce amyloid load by reducing production of the Aβ peptide or enhancing amyloid clearance by primary or secondary immunization have not proven successful in clinical trials. Interfering with the normal function of secretases and suboptimal timing of Aβ peptide removal have been put forward as possible explanations. Complement, an innate component of the immune system, has been found to modulate disease pathology and in particular neuronal loss in the AD mouse model but its mechanism of action is complex. C1Q has been shown to facilitate phagocytosis of Aβ peptide but its Ablation attenuates neuroinflammation. Experiments in AD mouse models show that inhibition of complement component C5a reduces amyloid deposition and alleviates neuroinflammation. Phagocytes including microglia, monocytes and neutrophils carry C5a receptors. Here, a widely used mouse model of AD, 5XFAD, was intermittently treated with the oral C5a receptor agonist EP67 and several neuronal and neuroinflammatory markers as well as memory function were assessed. EP67 treatment enhanced phagocytosis, resulting in a significant reduction of both fibrillar and non-fibrillar Aβ, reduced astrocytosis and preserved synaptic and neuronal markers as well as memory function. Timely and phasic recruitment of the innate immune system offers a new therapeutic avenue of treating pre-symptomatic Alzheimer disease., Competing Interests: The authors E.P. and T.K. have filed a PCT application on the use of the modified C5aR agonist EP67 in cerebral and peripheral amyloidoses (PCT/EP2018/053362). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Published
2019
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24. A novel mutation in the erythroid transcription factor KLF1 is likely responsible for ameliorating β-thalassemia major.

Author

Fanis P, Kousiappa I, Phylactides M, Kyrri A, Hadjigavriel M, Christou S, Sitarou M, and Kleanthous M

Subjects
Adult, Alleles, Biomarkers, DNA Mutational Analysis, Erythrocyte Indices, Female, Fetal Hemoglobin genetics, Genotype, Humans, Kruppel-Like Transcription Factors chemistry, Male, Middle Aged, Models, Molecular, Pedigree, Protein Conformation, Severity of Illness Index, Structure-Activity Relationship, Symptom Assessment, beta-Globins genetics, beta-Thalassemia blood, beta-Thalassemia diagnosis, Genetic Association Studies, Genetic Predisposition to Disease, Kruppel-Like Transcription Factors genetics, Mutation, Phenotype, beta-Thalassemia genetics
Abstract

We describe the identification of a novel missense mutation in the second zinc finger of KLF1 in two siblings who, based on their genotype, are predicted to suffer from beta thalassemia major but are, in fact, transfusion-free and in good health. These individuals, as well as two additional members of the same family also carrying this KLF1 mutation, exhibit high levels of fetal hemoglobin (HbF). KLF1 is an erythroid transcription factor, which plays a critical role in the regulation of the developmental switch between fetal and adult hemoglobin by regulating the expression of a multitude of genes including that of BCL11A. The mutation appears to be the main candidate responsible for the beta thalassemia-ameliorating effect as this segregates with the observed phenotype and also exogenous expression of the KLF1 mutant protein in human erythroid progenitor cells resulted in the induction of γ-globin, without, however, affecting BCL11A levels. This report adds to the weight of evidence that heterozygous KLF1 mutations can ameliorate the severity of the β-thalassemia major phenotype., (© 2019 The Authors. Human Mutation Published by Wiley Periodicals, Inc.)

Published
2019
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25. HIV-1 transmission networks across Cyprus (2010-2012).

Author

Kostrikis LG, Hezka J, Stylianou DC, Kostaki E, Andreou M, Kousiappa I, Paraskevis D, and Demetriades I

Subjects
Adolescent, Adult, Aged, Cyprus epidemiology, Drug Resistance, Viral genetics, Female, Geography, Medical, Homosexuality, Male, Humans, Male, Middle Aged, Molecular Epidemiology, Phylogeny, Prospective Studies, Young Adult, HIV Infections transmission, HIV-1 genetics
Abstract

A molecular epidemiology study of HIV-1 infection was conducted in one hundred diagnosed and untreated HIV-1-infected patients in Cyprus between 2010 and 2012, representing 65.4% of all the reported HIV-1 infections in Cyprus in this three-year period, using a previously defined enrolment strategy. Eighty-two patients were newly diagnosed (genotypic drug resistance testing within six months from diagnosis), and eighteen patients were HIV-1 diagnosed for a longer period or the diagnosis date was unknown. Phylogenetic trees of the pol sequences obtained in this study with reference sequences indicated that subtypes B and A1 were the most common subtypes present and accounted for 41.0 and 19.0% respectively, followed by subtype C (7.0%), F1 (8.0%), CRF02&#95;AG (4.0%), A2 (2.0%), other circulating recombinant forms (CRFs) (7.0%) and unknown recombinant forms (URFs) (12%). Most of the newly-diagnosed study subjects were Cypriots (63%), males (78%) with median age 39 (Interquartile Range, IQR 33-48) reporting having sex with other men (MSM) (51%). A high rate of clustered transmission of subtype B drug-sensitive strains to reverse transcriptase and protease inhibitors was observed among MSM, twenty-eight out of forty-one MSM study subjects (68.0%) infected were implicated in five transmission clusters, two of which are sub-subtype A1 and three of which are subtype B strains. The two largest MSM subtype B clusters included nine and eight Cypriot men, respectively, living in all major cities in Cyprus. There were only three newly diagnosed patients with transmitted drug resistant HIV-1 strains, one study subject from the United Kingdom infected with subtype B strain and one from Romania with sub-subtype A2 strain, both with PI drug resistance mutation M46L and one from Greece with sub-subtype A1 with non-nucleoside reverse transcriptase inhibitors (NNRTI) drug resistance mutation K103N.

Published
2018
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26. The molecular spectrum and distribution of haemoglobinopathies in Cyprus: a 20-year retrospective study.

Author

Kountouris P, Kousiappa I, Papasavva T, Christopoulos G, Pavlou E, Petrou M, Feleki X, Karitzie E, Phylactides M, Fanis P, Lederer CW, Kyrri AR, Kalogerou E, Makariou C, Ioannou C, Kythreotis L, Hadjilambi G, Andreou N, Pangalou E, Savvidou I, Angastiniotis M, Hadjigavriel M, Sitarou M, Kolnagou A, Kleanthous M, and Christou S

Subjects
Adolescent, Adult, Carrier State epidemiology, Cyprus epidemiology, Female, Gene Frequency, Hemoglobinopathies epidemiology, Humans, Male, Middle Aged, Mutation, Prevalence, Retrospective Studies, Young Adult, alpha-Thalassemia epidemiology, beta-Thalassemia epidemiology, Hemoglobinopathies genetics, alpha-Globins genetics, alpha-Thalassemia genetics, beta-Globins genetics, beta-Thalassemia genetics, delta-Globins genetics
Abstract

Haemoglobinopathies are the most common monogenic diseases, posing a major public health challenge worldwide. Cyprus has one the highest prevalences of thalassaemia in the world and has been the first country to introduce a successful population-wide prevention programme, based on premarital screening. In this study, we report the most significant and comprehensive update on the status of haemoglobinopathies in Cyprus for at least two decades. First, we identified and analysed all known 592 β-thalassaemia patients and 595 Hb H disease patients in Cyprus. Moreover, we report the molecular spectrum of α-, β- and δ-globin gene mutations in the population and their geographic distribution, using a set of 13824 carriers genotyped from 1995 to 2015, and estimate relative allele frequencies in carriers of β- and δ-globin gene mutations. Notably, several mutations are reported for the first time in the Cypriot population, whereas important differences are observed in the distribution of mutations across different districts of the island.

Published
2016
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27. Transmission of HIV Drug Resistance and the Predicted Effect on Current First-line Regimens in Europe.

Author

Hofstra LM, Sauvageot N, Albert J, Alexiev I, Garcia F, Struck D, Van de Vijver DAMC, Åsjö B, Beshkov D, Coughlan S, Descamps D, Griskevicius A, Hamouda O, Horban A, Van Kasteren M, Kolupajeva T, Kostrikis LG, Liitsola K, Linka M, Mor O, Nielsen C, Otelea D, Paraskevis D, Paredes R, Poljak M, Puchhammer-Stöckl E, Sönnerborg A, Staneková D, Stanojevic M, Van Laethem K, Zazzi M, Zidovec Lepej S, Boucher CAB, Schmit JC, Wensing AMJ, Puchhammer-Stockl E, Sarcletti M, Schmied B, Geit M, Balluch G, Vandamme AM, Vercauteren J, Derdelinckx I, Sasse A, Bogaert M, Ceunen H, De Roo A, De Wit S, Echahidi F, Fransen K, Goffard JC, Goubau P, Goudeseune E, Yombi JC, Lacor P, Liesnard C, Moutschen M, Pierard D, Rens R, Schrooten Y, Vaira D, Vandekerckhove LPR, Van den Heuvel A, Van Der Gucht B, Van Ranst M, Van Wijngaerden E, Vandercam B, Vekemans M, Verhofstede C, Clumeck N, Van Laethem K, Beshkov D, Alexiev I, Lepej SZ, Begovac J, Kostrikis L, Demetriades I, Kousiappa I, Demetriou V, Hezka J, Linka M, Maly M, Machala L, Nielsen C, Jørgensen LB, Gerstoft J, Mathiesen L, Pedersen C, Nielsen H, Laursen A, Kvinesdal B, Liitsola K, Ristola M, Suni J, Sutinen J, Descamps D, Assoumou L, Castor G, Grude M, Flandre P, Storto A, Hamouda O, Kücherer C, Berg T, Braun P, Poggensee G, Däumer M, Eberle J, Heiken H, Kaiser R, Knechten H, Korn K, Müller H, Neifer S, Schmidt B, Walter H, Gunsenheimer-Bartmeyer B, Harrer T, Paraskevis D, Hatzakis A, Zavitsanou A, Vassilakis A, Lazanas M, Chini M, Lioni A, Sakka V, Kourkounti S, Paparizos V, Antoniadou A, Papadopoulos A, Poulakou G, Katsarolis I, Protopapas K, Chryssos G, Drimis S, Gargalianos P, Xylomenos G, Lourida G, Psichogiou M, Daikos GL, Sipsas NV, Kontos A, Gamaletsou MN, Koratzanis G, Sambatakou H, Mariolis H, Skoutelis A, Papastamopoulos V, Georgiou O, Panagopoulos P, Maltezos E, Coughlan S, De Gascun C, Byrne C, Duffy M, Bergin C, Reidy D, Farrell G, Lambert J, O'Connor E, Rochford A, Low J, Coakely P, O'Dea S, Hall W, Mor O, Levi I, Chemtob D, Grossman Z, Zazzi M, de Luca A, Balotta C, Riva C, Mussini C, Caramma I, Capetti A, Colombo MC, Rossi C, Prati F, Tramuto F, Vitale F, Ciccozzi M, Angarano G, Rezza G, Kolupajeva T, Vasins O, Griskevicius A, Lipnickiene V, Schmit JC, Struck D, Sauvageot N, Hemmer R, Arendt V, Michaux C, Staub T, Sequin-Devaux C, Wensing AMJ, Boucher CAB, van de Vijver DAMC, van Kessel A, van Bentum PHM, Brinkman K, Connell BJ, van der Ende ME, Hoepelman IM, van Kasteren M, Kuipers M, Langebeek N, Richter C, Santegoets RMWJ, Schrijnders-Gudde L, Schuurman R, van de Ven BJM, Åsjö B, Kran AB, Ormaasen V, Aavitsland P, Horban A, Stanczak JJ, Stanczak GP, Firlag-Burkacka E, Wiercinska-Drapalo A, Jablonowska E, Maolepsza E, Leszczyszyn-Pynka M, Szata W, Camacho R, Palma C, Borges F, Paixão T, Duque V, Araújo F, Otelea D, Paraschiv S, Tudor AM, Cernat R, Chiriac C, Dumitrescu F, Prisecariu LJ, Stanojevic M, Jevtovic D, Salemovic D, Stanekova D, Habekova M, Chabadová Z, Drobkova T, Bukovinova P, Shunnar A, Truska P, Poljak M, Lunar M, Babic D, Tomazic J, Vidmar L, Vovko T, Karner P, Garcia F, Paredes R, Monge S, Moreno S, Del Amo J, Asensi V, Sirvent JL, de Mendoza C, Delgado R, Gutiérrez F, Berenguer J, Garcia-Bujalance S, Stella N, de Los Santos I, Blanco JR, Dalmau D, Rivero M, Segura F, Elías MJP, Alvarez M, Chueca N, Rodríguez-Martín C, Vidal C, Palomares JC, Viciana I, Viciana P, Cordoba J, Aguilera A, Domingo P, Galindo MJ, Miralles C, Del Pozo MA, Ribera E, Iribarren JA, Ruiz L, de la Torre J, Vidal F, Clotet B, Albert J, Heidarian A, Aperia-Peipke K, Axelsson M, Mild M, Karlsson A, Sönnerborg A, Thalme A, Navér L, Bratt G, Karlsson A, Blaxhult A, Gisslén M, Svennerholm B, Bergbrant I, Björkman P, Säll C, Mellgren Å, Lindholm A, Kuylenstierna N, Montelius R, Azimi F, Johansson B, Carlsson M, Johansson E, Ljungberg B, Ekvall H, Strand A, Mäkitalo S, Öberg S, Holmblad P, Höfer M, Holmberg H, Josefson P, and Ryding U

Subjects
Adult, Europe, Female, HIV Infections drug therapy, HIV Protease Inhibitors pharmacology, HIV-1 genetics, Humans, Male, Microbial Sensitivity Tests, Middle Aged, Mutation, Prevalence, Reverse Transcriptase Inhibitors pharmacology, Anti-HIV Agents pharmacology, Drug Resistance, Viral genetics, HIV Infections virology, HIV-1 drug effects
Abstract

Background: Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001., Methods: Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0., Results: The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%-9.5%) in 2008-2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones., Conclusions: Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affected., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.)

Published
2016
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28. Short communication: molecular epidemiology of HIV type 1 infection in northern Greece (2009-2010): evidence of a transmission cluster of HIV type 1 subtype A1 drug-resistant strains among men who have sex with men.

Author

Antoniadou ZA, Kousiappa I, Skoura L, Pilalas D, Metallidis S, Nicolaidis P, Malisiovas N, and Kostrikis LG

Subjects
Adult, Aged, Cluster Analysis, Female, Genotype, Greece epidemiology, HIV Infections virology, HIV-1 drug effects, HIV-1 genetics, Homosexuality, Male, Humans, Male, Middle Aged, Molecular Epidemiology, Molecular Sequence Data, Prospective Studies, Sequence Analysis, DNA, Sequence Homology, Young Adult, pol Gene Products, Human Immunodeficiency Virus genetics, Disease Transmission, Infectious, Drug Resistance, Viral, HIV Infections epidemiology, HIV Infections transmission, HIV-1 isolation & purification
Abstract

A prospective molecular epidemiology study of HIV-1 infection was conducted in newly diagnosed and antiretroviral-naive patients in Northern Greece between 2009 and 2010 using a predefined enrolling strategy. Phylogenetic trees of the pol sequences obtained in this study with reference sequences indicated that subtypes B and A1 were the most common subtypes present and accounted for 44.9% and 42.9%, respectively, followed by subtype C (3.1%), CRF02&#95;AG (4.1%), CRF04&#95;cpx (2.0%), and subtypes CRF01&#95;01, F1, and G (1.0%). A high rate of clustered transmission of subtype A1-resistant strains to reverse transcriptase (RT) inhibitors was observed among men having sex with men. Indeed, 15 out of 17 study subjects (88.2%) infected with transmitted drug resistance (TDR) strains were implicated in transmission clusters, 10 of whom (66.7%) were men who have sex with men (MSM), and were also infected with subsubtype A1 strains. The main cluster within subtype A1 (I) included eight men reporting having sex with men from Thessaloniki infected with dual-class RT-resistant strains carrying both T215C and Y181C mutations.

Published
2014
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29. Cellular HIV type 1 DNA levels are equivalent among drug-sensitive and drug-resistant strains in newly diagnosed and antiretroviral naive patients.

Author

Antoniadou ZA, Hezka J, Kousiappa I, Mamais I, Skoura L, Pilalas D, Metallidis S, Nicolaidis P, Malisiovas N, and Kostrikis LG

Subjects
Adult, DNA, Viral chemistry, DNA, Viral genetics, Female, Greece, HIV-1 genetics, HIV-1 physiology, Humans, Male, Molecular Sequence Data, Proviruses genetics, Sequence Analysis, DNA, Viral Tropism, DNA, Viral analysis, Drug Resistance, Viral, HIV Infections virology, HIV-1 isolation & purification, Proviruses isolation & purification, Viral Load
Abstract

The emergence of resistance against current antiretroviral drugs to human immunodeficiency virus type 1 (HIV-1) is an increasingly important concern to the continuous success of antiretroviral therapy to HIV-1-infected patients. In the past decade, a number of studies reported that the prevalence of transmitted drug resistance among newly diagnosed patients has reached an overall 9% prevalence worldwide. Also, a number of studies using longitudinal HIV-1 patient study cohorts demonstrated that the cellular HIV-1 DNA level in peripheral blood mononuclear cells (PBMCs) has a prognostic value for the progression of HIV-1 disease independently of plasma HIV-1 RNA load and CD4 count. Using a previously established molecular-beacon-based real-time PCR methodology, cellular HIV-1 DNA levels were quantified in newly diagnosed and antiretroviral-naive patients in Northern Greece recruited between 2009 and 2010 using a predefined enrolling strategy, in an effort to investigate whether there is any relationship between cellular HIV-1 DNA levels and HIV-1 transmitted drug resistance. As part of the same study, DNA sequences encoding the env (C2-C5 region of gp120) were also amplified from PBMC-extracted DNA in order to determine the genotypic coreceptor tropism and genetic subtype. Cellular HIV-1 DNA levels had a median of 3.309 log10 HIV-1 copies per 10(6) PBMCs and demonstrated no correlation between cellular HIV-1 DNA levels and HIV-1 transmitted drug resistance. An absence of association between cellular HIV-1 DNA levels with plasma viral HIV-1 RNA load and CD4 levels was also found reconfirming the previously published study. Genotypic analysis of coreceptor tropism indicated that 96% of samples, independently of the presence or not of genotypic drug resistance, were CCR5-tropic. Overall, the findings reconfirmed the previously proposed proposition that transmitted drug resistance does not have an impact on disease progression in HIV-1-infected individuals. Also, CCR5 coreceptor tropism dominance suggests that both drug-resistant and drug-sensitive strains behave similarly in early infection in newly diagnosed patients.

Published
2014
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30. Genotyping of BCL11A and HBS1L-MYB SNPs associated with fetal haemoglobin levels: a SNaPshot minisequencing approach.

Author

Fanis P, Kousiappa I, Phylactides M, and Kleanthous M

Subjects
Carrier Proteins metabolism, DNA, Intergenic metabolism, Fetal Hemoglobin analysis, GTP-Binding Proteins genetics, Genotype, HSP70 Heat-Shock Proteins genetics, Humans, Multiplex Polymerase Chain Reaction, Nuclear Proteins metabolism, Peptide Elongation Factors genetics, Proto-Oncogene Proteins c-myb genetics, Repressor Proteins, Carrier Proteins genetics, DNA, Intergenic genetics, Fetal Hemoglobin genetics, Nuclear Proteins genetics, Polymorphism, Single Nucleotide, Sequence Analysis, DNA methods
Abstract

Background: B-thalassaemia and sickle cell disease (SCD) are two of the most common monogenic diseases that are found in many populations worldwide. In both disorders the clinical severity is highly variable, with the persistence of fetal haemoglobin (HbF) being one of the major ameliorating factors. HbF levels are affected by, amongst other factors, single nucleotide polymorphisms (SNPs) at the BCL11A gene and the HBS1L-MYB intergenic region, which are located outside the β-globin locus. For this reason, we developed two multiplex assays that allow the genotyping of SNPs at these two genomic regions which have been shown to be associated with variable HbF levels in different populations., Results: Two multiplex assays based on the SNaPshot minisequencing approach were developed. The two assays can be used to simultaneous genotype twelve SNPs at the BCL11A gene and sixteen SNPs at HBS1L-MYB intergenic region which were shown to modify HbF levels. The different genotypes can be determined based on the position and the fluorescent colour of the peaks in a single electropherogram. DNA sequencing and restriction fragment length polymorphism (PCR-RFLP) assays were used to verify genotyping results obtained by SNaPshot minisequencing., Conclusions: In summary, we propose two multiplex assays based on the SNaPshot minisequencing approach for the simultaneous identification of SNPs located at the BCL11A gene and HBS1L-MYB intergenic region which have an effect on HbF levels. The assays can be easily applied for accurate, time and cost efficient genotyping of the selected SNPs in various populations.

Published
2014
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31. Molecular characterization of HIV type 1 strains from newly diagnosed patients in Cyprus (2007-2009) recovers multiple clades including unique recombinant strains and lack of transmitted drug resistance.

Author

Kousiappa I, Achilleos C, Hezka J, Lazarou Y, Othonos K, Demetriades I, and Kostrikis LG

Subjects
Adult, Anti-HIV Agents pharmacology, Child, Cyprus epidemiology, Female, HIV Infections epidemiology, HIV Infections virology, HIV-1 drug effects, HIV-1 isolation & purification, Humans, Male, Microbial Sensitivity Tests methods, Middle Aged, Molecular Sequence Data, Mutation, Phylogeny, Sequence Analysis, DNA, Drug Resistance, Viral genetics, Genetic Variation, HIV Infections diagnosis, HIV-1 classification, HIV-1 genetics, Recombination, Genetic
Abstract

HIV-1 evolution generates substantial genetic diversity among isolates, the majority of which are represented in areas where multiple strains cocirculate. A heterogeneous genetic HIV-1 pool has been found in Cyprus, directing us to determine the dynamics of the local HIV-1 infection by characterizing strains isolated from 74 subjects during 2007-2009, representing 88% of the known-living HIV-1-infected population, of whom 53 are newly diagnosed therapy-naive patients and 21 are chronic patients, according to the European HIV Resistance guidelines. Near full-length genome sequences were amplified by RT-nested PCR using diluted RNA from all HIV-1 seropositives and sequenced using a newly designed assay. Resistant mutations were not found among the population of the newly diagnosed therapy-naive patients either to protease, reverse transcriptase, or integrase inhibitors. Phylogenetic analyses indicated subtype B as the main subtype (48.6%), followed by subtype A (18.9%), subtype C (10.8%), CRF02&#95;AG (8.1%), CRF11&#95;cpx (2.7%), and (sub)subtype F1 and CRF37&#95;cpx (1.4% each). Six HIV-1 isolates (8.1%) were not classified in any pure (sub)subtype or circulating recombinant form (CRF). Complete phylogenetic and bootscanning analyses revealed that each isolate had a new, unique recombinant pattern and is distinct from all other CRFs or unique recombinant forms (URFs) reported so far. Two of the six isolates have the same mosaic pattern. Analogous to results of the earlier epidemiological studies, this study expands on the HIV-1 sequence database and reveals the high degree of diversity of HIV-1 infection in Cyprus.

Published
2011
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32. Cellular HIV-1 DNA levels in drug sensitive strains are equivalent to those in drug resistant strains in newly-diagnosed patients in Europe.

Author

Demetriou VL, van de Vijver DA, Kousiappa I, Balotta C, Clotet B, Grossman Z, Jørgensen LB, Lepej SZ, Levy I, Nielsen C, Paraskevis D, Poljak M, Roman F, Ruiz L, Schmidt JC, Vandamme AM, Van Laethem K, Vercauteren J, and Kostrikis LG

Subjects
Adult, Alleles, Base Sequence, DNA Primers, Europe, Female, Humans, Male, Polymerase Chain Reaction, Receptors, CCR5 genetics, Sequence Homology, Nucleic Acid, Viral Load, Viral Tropism, DNA, Viral genetics, Drug Resistance, Viral, HIV Infections virology, HIV-1 genetics
Abstract

Background: HIV-1 genotypic drug resistance is an important threat to the success of antiretroviral therapy and transmitted resistance has reached 9% prevalence in Europe. Studies have demonstrated that HIV-1 DNA load in peripheral blood mononuclear cells (PBMC) have a predictive value for disease progression, independently of CD4 counts and plasma viral load., Methodology/principal Findings: Molecular-beacon-based real-time PCR was used to measure HIV-1 second template switch (STS) DNA in PBMC in newly-diagnosed HIV-1 patients across Europe. These patients were representative for the HIV-1 epidemic in the participating countries and were carrying either drug-resistant or sensitive viral strains. The assay design was improved from a previous version to specifically detect M-group HIV-1 and human CCR5 alleles. The findings resulted in a median of 3.32 log(10) HIV-1 copies/10(6) PBMC and demonstrated for the first time no correlation between cellular HIV-1 DNA load and transmitted drug-resistance. A weak association between cellular HIV-1 DNA levels with plasma viral RNA load and CD4(+) T-cell counts was also reconfirmed. Co-receptor tropism for 91% of samples, whether or not they conferred resistance, was CCR5. A comparison of pol sequences derived from RNA and DNA, resulted in a high similarity between the two., Conclusions/significance: An improved molecular-beacon-based real-time PCR assay is reported for the measurement of HIV-1 DNA in PBMC and has investigated the association between cellular HIV-1 DNA levels and transmitted resistance to antiretroviral therapy in newly-diagnosed patients from across Europe. The findings show no correlation between these two parameters, suggesting that transmitted resistance does not impact disease progression in HIV-1 infected individuals. The CCR5 co-receptor tropism predominance implies that both resistant and non-resistant strains behave similarly in early infection. Furthermore, a correlation found between RNA- and DNA-derived sequences in the pol region suggests that genotypic drug-resistance testing could be carried out on either template.

Published
2010
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33. Near full-length genetic analysis of HIV sequences derived from Cyprus: evidence of a highly polyphyletic and evolving infection.

Author

Kousiappa I, Van De Vijver DA, and Kostrikis LG

Subjects
Adult, Aged, Aged, 80 and over, Cyprus epidemiology, DNA, Viral analysis, DNA, Viral genetics, Female, Genes, Viral, Genetic Variation, HIV-1 isolation & purification, Humans, Male, Middle Aged, Molecular Sequence Data, Phylogeny, Sequence Analysis, DNA, Evolution, Molecular, Genome, Viral, HIV Infections epidemiology, HIV Infections genetics, HIV Infections virology, HIV-1 genetics
Abstract

The molecular epidemiology of HIV-1 infection was previously studied in Cyprus but the degree of HIV-1 diversity has remained indefinable. The main objective of the present study is to examine HIV-1 strains isolated from 77 HIV-1-infected individuals representing 38% of the known infected population in Cyprus in the period 1986 to 2006. DNA of the near full-length genome encoding gag, pol, vif, vpr, vpu, tat, rev, env, and 5'-end of nef was amplified by nested PCR/RT-PCR from all HIV-1 seropositives and sequenced using a newly designed assay. Detailed phylogenetic and bootscanning analyses were performed to determine phylogenetic associations and subtype assignments. Phylogenetic analyses of the obtained viral sequences indicated that subtype B was the dominant subtype (61%), followed by subtype A (23.3%), subtype C (5.2%), CRF02&#95;AG (3.9%), and subtype D, CRF01&#95;AE, and CRF04&#95;cpx (1.3% each). Two HIV-1 isolates (2.6%), originating from the Democratic Republic of Congo (DRC), were not classified in any pure (sub)subtype or circulating recombinant form (CRF). Complete phylogenetic and bootscanning analyses revealed that one of these isolates had a new, unique recombinant pattern, comprising segments of subtypes D and G, and is distinct from any other CRFs or URFs reported so far. Detailed analyses of the sequence of the second isolate, which could not be classified, reveal that it is close to subtype K reference sequences but clusters near the root of the clade. At least two epidemiologically unrelated HIV-1 seropositives with an HIV-1 variant similar to this isolate are required to designate this variant as a novel HIV-1 subtype or subsubtype of subtype K. Analogous to results of the earlier epidemiological studies, these data exhibit the extensive heterogeneity of HIV-1 infection in Cyprus, which is being fueled by a continuous entry of new strains from other countries, creating an evolving and polyphyletic infection.

Published
2009
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34. Implications of HIV-1 M group polymorphisms on integrase inhibitor efficacy and resistance: genetic and structural in silico analyses.

Author

Loizidou EZ, Kousiappa I, Zeinalipour-Yazdi CD, Van de Vijver DA, and Kostrikis LG

Subjects
Binding Sites, HIV Integrase Inhibitors pharmacology, HIV-1 drug effects, Models, Molecular, Mutation, Polymorphism, Genetic, Protein Binding, Protein Conformation, Pyrrolidinones pharmacology, Raltegravir Potassium, Drug Resistance, Viral, HIV Integrase genetics, HIV Integrase Inhibitors chemistry, HIV-1 enzymology, Pyrrolidinones chemistry
Abstract

The extensive polymorphisms among HIV-1 subtypes have been implicated in drug resistance development. Integrase inhibitors represent the latest addition to the treatment of HIV-1, and their efficacy and resistance patterns among M group strains are currently under investigation. This study analyzed the intersubtype variation within 108 integrase sequences from seven subtypes. The residues associated with catalytic activity and primary resistance to raltegravir were highly conserved among all strains. Variations were observed in residues associated with secondary resistance. Molecular modeling studies indicated a two-way binding mode of raltegravir that explains the resistance pathways and the implication of nonconservative mutations in integrase-raltegravir interactions.

Published
2009
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35. Genetic analysis of HIV type 1 strains from newly infected untreated patients in cyprus: high genetic diversity and low prevalence of drug resistance.

Author

Kousiappa I, van de Vijver DA, Demetriades I, and Kostrikis LG

Subjects
Adult, Amino Acid Substitution genetics, Animals, Cluster Analysis, Cyprus epidemiology, Female, Genotype, HIV-1 genetics, HIV-1 isolation & purification, Humans, Male, Middle Aged, Molecular Epidemiology, Molecular Sequence Data, Mutation, Missense, Phylogeny, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, DNA, Sequence Homology, Viral Proteins genetics, Drug Resistance, Viral, HIV Infections epidemiology, HIV Infections virology, HIV-1 classification, HIV-1 drug effects, Polymorphism, Genetic
Abstract

Abstract The molecular epidemiology of HIV-1 infection was first studied in Cyprus in the mid-1990s, but the extent of HIV-1 diversity and the prevalence of drug resistance have remained elusive. In an effort to address this issue, the present study examined HIV-1 strains isolated from 37 newly diagnosed untreated HIV-1 patients, representing 72% of the total number of newly diagnosed and drug-naive patients in the period 2003 to 2006. DNA sequences encoding the gag (p17, p24, p2, p7, p1, and p6), pol (protease and reverse transcriptase), and env (gp160) regions were amplified by RT-PCR from plasma HIV-1 RNA from all patients and sequenced using a newly designed methodology. All amplified products were studied according to established genetic methodologies to determine the genetic subtype and the prevalence of drug-resistance-associated mutations to currently available antiretroviral drugs. Analyses of the obtained viral sequences indicated that subtype A was the most common subtype present and accounted for 38% of the infections followed by subtype B (35%), subtype C (13%), CRF02&#95;AG (8%), and subtypes D and CRF01&#95;AE (3% each). One patient (2.7%) had an M41L/M and another patient (2.7%) an M184V amino acid substitution in the reverse transcriptase (RT) associated with high-level resistance to RT inhibitors. There were no patients with resistant mutations to protease inhibitors (PI). Additionally, one patient (2.7%) had an L44M amino acid substitution within the HR1 region of gp41 conferring resistance to the enfuvirtide (T20) fusion inhibitor. Similar to results of the 1994 molecular epidemiological study, these data demonstrate the extensive heterogeneity of HIV-1 infection in Cyprus and the low prevalence of transmitted resistance to current HIV-1 antiretroviral drugs. Taken together, these findings demonstrate that HIV-1 infection in Cyprus is being replenished by a continuous influx of new strains from many countries, establishing an ever-evolving and polyphyletic infection in the island.

Published
2009
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