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1. Low frequency of genotypic resistance in HIV-1-infected patients failing an atazanavir-containing regimen: a clinical cohort study

Author

Dolling, David I, Dunn, David T, Sutherland, Katherine A, Pillay, Deenan, Mbisa, Jean L, Parry, Chris M, Post, Frank A, Sabin, Caroline A, Cane, Patricia A, Aitken, Celia, Asboe, David, Webster, Daniel, Cane, Patricia, Castro, Hannah, Dunn, David, Dolling, David, Chadwick, David, Churchill, Duncan, Clark, Duncan, Collins, Simon, Delpech, Valerie, Geretti, Anna Maria, Goldberg, David, Hale, Antony, Hué, Stéphane, Kaye, Steve, Kellam, Paul, Lazarus, Linda, Leigh-Brown, Andrew, Mackie, Nicola, Orkin, Chloe, Rice, Philip, Phillips, Andrew, Sabin, Caroline, Smit, Erasmus, Templeton, Kate, Tilston, Peter, Tong, William, Williams, Ian, Zhang, Hongyi, Zuckerman, Mark, Greatorex, Jane, Wildfire, Adrian, O'Shea, Siobhan, Mullen, Jane, Mbisa, Tamyo, Cox, Alison, Tandy, Richard, Hale, Tony, Fawcett, Tracy, Hopkins, Mark, Ashton, Lynn, Booth, Claire, Garcia-Diaz, Ana, Shepherd, Jill, Schmid, Matthias L, Payne, Brendan, Hay, Phillip, Rice, Phillip, Paynter, Mary, Bibby, David, Kirk, Stuart, MacLean, Alasdair, Gunson, Rory, Coughlin, Kate, Fearnhill, Esther, Fradette, Lorraine, Porter, Kholoud, Ainsworth, Jonathan, Anderson, Jane, Babiker, Abdel, Fisher, Martin, Gazzard, Brian, Gilson, Richard, Gompels, Mark, Hill, Teresa, Johnson, Margaret, Kegg, Stephen, Leen, Clifford, Nelson, Mark, Palfreeman, Adrian, Post, Frank, Sachikonye, Memory, Schwenk, Achim, Walsh, John, Huntington, Susie, Jose, Sophie, Thornton, Alicia, Glabay, Adam, Orkin, C, Garrett, N, Lynch, J, Hand, J, de Souza, C, Fisher, M, Perry, N, Tilbury, S, Gazzard, B, and Nelson, M

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Infectious Diseases, Antimicrobial Resistance, Clinical Research, Infection, Adult, Anti-HIV Agents, Atazanavir Sulfate, Cohort Studies, Drug Resistance, Viral, Female, HIV Infections, HIV Protease, HIV-1, Humans, Male, Medication Adherence, Middle Aged, Mutation Rate, Mutation, Missense, Oligopeptides, Pyridines, Treatment Failure, United States, UK HIV Drug Resistance Database, UK Collaborative HIV Cohort Study, HIV, drug resistance mutations, naive patients, protease inhibitors, virological failure, Microbiology, Pharmacology and Pharmaceutical Sciences, Clinical sciences, Pharmacology and pharmaceutical sciences
Abstract

ObjectivesTo determine protease mutations that develop at viral failure for protease inhibitor (PI)-naive patients on a regimen containing the PI atazanavir.MethodsResistance tests on patients failing atazanavir, conducted as part of routine clinical care in a multicentre observational study, were randomly matched by subtype to resistance tests from PI-naive controls to account for natural polymorphisms. Mutations from the consensus B sequence across the protease region were analysed for association and defined using the IAS-USA 2011 classification list.ResultsFour hundred and five of 2528 (16%) patients failed therapy containing atazanavir as a first PI over a median (IQR) follow-up of 1.76 (0.84-3.15) years and 322 resistance tests were available for analysis. Recognized major atazanavir mutations were found in six atazanavir-experienced patients (P < 0.001), including I50L and N88S. The minor mutations most strongly associated with atazanavir experience were M36I, M46I, F53L, A71V, V82T and I85V (P < 0.05). Multiple novel mutations, I15S, L19T, K43T, L63P/V, K70Q, V77I and L89I/T/V, were also associated with atazanavir experience.ConclusionsViral failure on atazanavir-containing regimens was not common and major resistance mutations were rare, suggesting that adherence may be a major contributor to viral failure. Novel mutations were described that have not been previously documented.

Published
2013

4. Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission

Author

Aggarwal, Dinesh, Warne, Ben, Jahun, Aminu S., Hamilton, William L., Fieldman, Thomas, du Plessis, Louis, Hill, Verity, Blane, Beth, Watkins, Emmeline, Wright, Elizabeth, Hall, Grant, Ludden, Catherine, Myers, Richard, Hosmillo, Myra, Chaudhry, Yasmin, Pinckert, Malte L., Georgana, Iliana, Izuagbe, Rhys, Leek, Danielle, Nsonwu, Olisaeloka, Hughes, Gareth J., Packer, Simon, Page, Andrew J., Metaxaki, Marina, Fuller, Stewart, Weale, Gillian, Holgate, Jon, Brown, Christopher A., Orton, Alexandra, Douthwaite, Julie, Rees, Steve, Brown, Christopher, Clark, Roger, Jones, Daniel R., Kuenzi, Fred, Rankin, Jennifer, Waddell, Ian, Maxwell, Patrick, Matheson, Nicholas, Abell, Chris, Braithwaite, Vickie, Brierley, Craig, Crowcroft, Jon, Dahal, Aastha, Faulkner, Kathryn, Glover, Michael, Goodfellow, Ian, Greatorex, Jane, James, Laura, Lehner, Paul, Leslie, Ian, Liddell, Kathleen, Margolis, Ben, Morgan, Sally, Sheridan, Linda, Valletta, Sally, Vignoles, Anna, Vinnell, Martin, Wills, Mark, Hilborne, Sarah, Berry, Sarah, Kahkeshi, Mahin Bagheri, Hancock, Dawn, Winster, Jennifer, Enright, Jessica, Samworth, Richard, Samtani, Vijay, Ahmadi-Assalemi, Gabriela, Feather, Tom, Goodall, Robin, Hoensch, Steve, Johnson, Dean, Hunt, Martin, Mathieson, Nick, Nikitina, Katya, Sheldrake, Zara, Keen, Martin, Sato, Aris, Connor, David, Tolhurst, Jonathan, Williman, Jack, Hollamby, Victoria, Jordan, Sinead, Fatseas, Tania, Taylor, Peter, Georgiou, Christine, Caspersz, Michelle, McNulty, Claire, Davies, Richard, Clarke, Rebecca, Danaei, Darius, Dyer, Rory, Glew, Rob, Lambson, Oliver, Gibbs, Karen, Mozdzen, Barbara, Raub, Gabor, Radecki, Asako, White, Phil, Hughes, Robert, Gransden, Lucie, Ceaser, Matt, Sing, Robert, Wilson, Karl, Parlikad, Ajith, Dhada, Maharshi, Ridgman, Tom, Mungovan, Diane, Matthews, Steve, Searle, Paul, Mills, John, Neely, Andy, Henderson, Robert, Murphy, Edna, Russell, Matthew, Freeling, Anthony, Poppitt, Steve, Tynan, Jo, Knapton, James, Marchetti, Filippo, Angelis, Daniela De, Feltwell, Theresa, Hadjirin, Nazreen F., Jahun, Aminu, Pinckert, Malte, Shaw, Ashley, Chaudhry, Afzal, Brown, Nicholas M., Mactavous, Lenette, Hannan, Sophie, Hosaja, Aleksandra, Leong, Clare, Wright, Jo, Quinnell, Natalie, Workman, Chris, Ferris, Mark, Wright, Giles, Brooks, Ellena, Carabelli, Alessandro M., Churcher, Carol M., Galai, Katerina, Girgis, Sophia T., Gupta, Ravi K., McManus, Georgina M., Palmer, Sophie, Peacock, Sharon J., Smith, Kim S., Allara, Elias, Bibby, David, Bishop, Chloe, Bosworth, Andrew, Bradshaw, Daniel, Chalker, Vicki, Chand, Meera, Dabrera, Gavin, Ellaby, Nicholas, Gallagher, Eileen, Groves, Natalie, Harrison, Ian, Hartman, Hassan, Hopes, Richard, Hubb, Jonathan, Hutchings, Stephanie, Lackenby, Angie, Ledesma, Juan, Lee, David, Manesis, Nikos, Manso, Carmen, Mbisa, Tamyo, Miah, Shahjahan, Muir, Peter, Osman, Husam, Patel, Vineet, Pearson, Clare, Platt, Steven, Pymont, Hannah M., Ramsay, Mary, Robinson, Esther, Schaefer, Ulf, Thornton, Alicia, Twohig, Katherine A., Vipond, Ian B., Williams, David, Aigrain, Louise, Alderton, Alex, Amato, Roberto, Ariani, Cristina V., Barrett, Jeff, Bassett, Andrew R., Beale, Mathew A., Beaver, Charlotte, Bellis, Katherine L., Betteridge, Emma, Bonfield, James, Bronner, Iraad F., Chapman, Michael H. S., Danesh, John, Davies, Robert, Dorman, Matthew J., Drury, Eleanor, Durham, Jillian, Farr, Ben W., Foulser, Luke, Goncalves, Sonia, Goodwin, Scott, Gourtovaia, Marina, Jackson, David K., James, Keith, Jamrozy, Dorota, Johnston, Ian, Kane, Leanne, Kay, Sally, Keatley, Jon-Paul, Kwiatkowski, Dominic, Langford, Cordelia F., Lawniczak, Mara, Lensing, Stefanie V., Leonard, Steven, Letchford, Laura, Lewis, Kevin, Liddle, Jennifier, Livett, Rich, Lo, Stephanie, Makunin, Alex, Martincorena, Inigo, McCarthy, Shane, McGuigan, Samantha, Moll, Robin J., Nelson, Rachel, Oliver, Karen, Palmer, Steve, Park, Naomi R., Patel, Minal, Prestwood, Liam, Puethe, Christoph, Quail, Michael A., Rajan, Diana, Rajatileka, Shavanthi, Redshaw, Nicholas M., Scott, Carol, Shirley, Lesley, Sillitoe, John, Thurston, Scott A. J., Tonkin-Hill, Gerry, Tovar-Corona, Jaime M., Weldon, Danni, Whitwham, Andrew, Attwood, Stephen W., Zamudio, Marina Escalera, Francois, Sarah, Gutierrez, Bernardo, Kraemer, Moritz U. G., Raghwani, Jayna, Vasylyeva, Tetyana I., Zarebski, Alex E., Alikhan, Nabil-Fareed, Aydin, Alp, Baker, David J., de Oliveira Martins, Leonardo, Kay, Gemma L., Le-Viet, Thanh, Mather, Alison E., Meadows, Lizzie, O’Grady, Justin, Rudder, Steven, Trotter, Alexander J., Illingworth, Chris J., Jackson, Chris, Aranday-Cortes, Elihu, Asamaphan, Patawee, Broos, Alice, Carmichael, Stephen N., da Silva Filipe, Ana, Hughes, Joseph, Jesudason, Natasha G., Johnson, Natasha, Li, Kathy K., Mair, Daniel, Nichols, Jenna, Nickbakhsh, Seema, Niebel, Marc O., Nomikou, Kyriaki, Orton, Richard J., Robertson, David L., Shah, Rajiv N., Shepherd, James G., Singer, Joshua B., Starinskij, Igor, Thomson, Emma C., Tong, Lily, Vattipally, Sreenu, Ash, Amy, Koshy, Cherian, Cortes, Nick, Kidd, Stephen, Lynch, Jessica, Moore, Nathan, Mori, Matilde, Wise, Emma, Curran, Tanya, Fairley, Derek J., McKenna, James P., Adams, Helen, Bonsall, David, Fraser, Christophe, Golubchik, Tanya, Cogger, Benjamin J., Hassan-Ibrahim, Mohammed O., Malone, Cassandra S., Reynolds, Nicola, Wantoch, Michelle, Afifi, Safiah, Beer, Robert, John, Michaela, Maksimovic, Joshua, McCluggage, Kathryn, Morgan, Sian, Spellman, Karla, Bresner, Catherine, Connor, Thomas R., Fuller, William, Guest, Martyn, Gulliver, Huw, Kitchen, Christine, Marchbank, Angela, Merrick, Ian, Munn, Robert, Price, Anna, Southgate, Joel, Workman, Trudy, Patel, Amita, Snell, Luke B., Batra, Rahul, Charalampous, Themoula, Edgeworth, Jonathan, Nebbia, Gaia, Beckett, Angela H., Robson, Samuel C., Aanensen, David M., Abudahab, Khalil, Menegazzo, Mirko, Taylor, Ben E. W., Underwood, Anthony P., Yeats, Corin A., Berry, Louise, Boswell, Tim, Clark, Gemma, Fleming, Vicki M., Howson-Wells, Hannah C., Jones, Carl, Joseph, Amelia, Khakh, Manjinder, Lister, Michelle M., Smith, Wendy, Willingham, Iona, Bird, Paul, Fallon, Karlie, Helmer, Thomas, Holmes, Christopher, Tang, Julian, Blakey, Victoria, Campbell, Sharon, Raviprakash, Veena, Sheriff, Nicola, Williams, Lesley-Anne, Carlile, Matthew, Debebe, Johnny, Holmes, Nadine, Loose, Matthew W., Moore, Christopher, Sang, Fei, Wright, Victoria, Coll, Francesc, Betancor, Gilberto, Signell, Adrian W., Wilson, Harry D., Davis, Thomas, Eldirdiri, Sahar, Kenyon, Anita, Torok, M. Estee, Lowe, Hannah, Moses, Samuel, Bedford, Luke, Moore, Jonathan, Stonehouse, Susanne, Awan, Ali R., Fisher, Chloe L., BoYes, John, Atkinson, Laura, Breuer, Judith, Brown, Julianne R., Harris, Kathryn A., Lee, Jack C. D., Shah, Divya, Storey, Nathaniel, Flaviani, Flavia, Alcolea-Medina, Adela, Vernet, Gabrielle, Williams, Rebecca, Chapman, Michael R., Chatterton, Wendy, Heaney, Judith, Levett, Lisa J., Pusok, Monika, Xu-McCrae, Li, Bashton, Matthew, Smith, Darren, Young, Greg, Bolt, Frances, Cox, Alison, Holmes, Alison, Madona, Pinglawathee, Mookerjee, Siddharth, Price, James, Randell, Paul A., Boyd, Olivia, Nascimento, Fabricia F., Geidelberg, Lily, Johnson, Rob, Jorgensen, David, Ragonnet-Cronin, Manon, Rowan, Aileen, Siveroni, Igor, Taylor, Graham P., Volz, Erik M., Smollett, Katherine L., Loman, Nicholas J., McMurray, Claire, McNally, Alan, Nicholls, Sam, Poplawski, Radoslaw, Quick, Joshua, Rowe, Will, Stockton, Joanne, Nunez, Rocio T. Martinez, Breen, Cassie, Cowell, Angela, Mason, Jenifer, O’Toole, Elaine, Robinson, Trevor I., Watts, Joanne, Sluga, Graciela, Ahmad, Shazaad S. Y., George, Ryan P., Machin, Nicholas W., Halstead, Fenella, Hogsden, Wendy, Sivaprakasam, Venkat, Carden, Holli, Hale, Antony D., Harper, Katherine L., Macfarlane-Smith, Louissa R., Burton-Fanning, Shirelle, Collins, Jennifer, Eltringham, Gary, Payne, Brendan AI., Taha, Yusri, Waugh, Sheila, O’Brien, Sarah, Rushton, Steven, Blacow, Rachel, Bradley, Amanda, Maclean, Alasdair, Mollett, Guy, Dewar, Rebecca, McHugh, Martin P., Templeton, Kate E., Wastenge, Elizabeth, Coupland, Lindsay, Dervisevic, Samir, Meader, Emma J., Stanley, Rachael, Smith, Louise, Barton, Edward, Graham, Clive, Padgett, Debra, Scott, Garren, Greenaway, Jane, Swindells, Emma, McCann, Clare, Nelson, Andrew, Yew, Wen Chyin, Andersson, Monique, Crook, Derrick, Eyre, David, Justice, Anita, Peto, Timothy, Duckworth, Nichola, Sloan, Tim J., Walsh, Sarah, Bicknell, Kelly, Chauhan, Anoop J., Elliott, Scott, Glaysher, Sharon, Impey, Robert, Lloyd, Allyson, Wyllie, Sarah, Levene, Nick, Monaghan, Lynn, Bradley, Declan T., Wyatt, Tim, Curran, Martin D., Parmar, Surendra, Holden, Matthew T. G., Shaaban, Sharif, Adams, Alexander, Asad, Hibo, Birchley, Alec, Bull, Matthew, Coombes, Jason, Corden, Sally, Cottrell, Simon, Craine, Noel, Cronin, Michelle, Davies, Alisha, Lacy, Elen De, Downing, Fatima, Edwards, Sue, Evans, Johnathan M., Fina, Laia, Gaskin, Amy, Gatica-Wilcox, Bree, Gifford, Laura, Gilbert, Lauren, Graham, Lee, Heyburn, David, Hilvers, Ember, Howe, Robin, Jones, Hannah, Jones, Rachel, Jones, Sophie, Kumziene-SummerhaYes, Sara, McKerr, Caoimhe, Moore, Catherine, Morgan, Mari, Pacchiarini, Nicole, Perry, Malorie, Plimmer, Amy, Rey, Sara, Shankar, Giri, Taylor, Sarah, Watkins, Joanne, Williams, Chris, Casey, Anna, Ratcliffe, Liz, Acheson, Erwan, Molnar, Zoltan, Simpson, David A., Thompson, Thomas, Auckland, Cressida, Ellard, Sian, Jones, Christopher R., Knight, Bridget A., Masoli, Jane A. H., Haque, Tanzina, Hart, Jennifer, Irish-Tavares, Dianne, Mahungu, Tabitha W., Witele, Eric, Dadrah, Ashok, Fenton, Melisa L., Saluja, Tranprit, Symmonds, Amanda, Bourgeois, Yann, Scarlett, Garry P., Cook, Kate, Dent, Hannah, Fearn, Christopher, Goudarzi, Salman, Loveson, Katie F., Paul, Hannah, Evans, Cariad, Johnson, Kate, Partridge, David G., Raza, Mohammad, Baker, Paul, Bonner, Stephen, Essex, Sarah, Liggett, Steven, Lyons, Ronan A., Mahanama, Adhyana I. K., Saeed, Kordo, Samaraweera, Buddhini, Silveira, Siona, Wilson-Davies, Eleri, Emanuela, P., Bayzid, Nadua, Cotic, Marius, Ensell, Leah, Hartley, John A., Jannoo, Riaz, Karamani, Angeliki, Kristiansen, Mark, Lowe, Helen L., Roy, Sunando, Westhorpe, Adam P., Williams, Rachel J., Williams, Charlotte A., Jeremiah, Sarah, Prieto, Jacqui A., Berry, Lisa, Grammatopoulos, Dimitris, Jones, Katie, Pandey, Sarojini, Beggs, Andrew, Richter, Alex, Ashcroft, Fiona, Best, Angus, Crawford, Liam, Cumley, Nicola, Mayhew, Megan, Megram, Oliver, Mirza, Jeremy, Moles-Garcia, Emma, Percival, Benita, Bucca, Giselda, Hesketh, Andrew R., Smith, Colin P., Davidson, Rose K., Balcazar, Carlos E., Gallagher, Michael D., O’Toole, Áine, Rambaut, Andrew, Rooke, Stefan, Stanton, Thomas D., Williams, Thomas, Williamson, Kathleen A., Bewshea, Claire M., Farbos, Audrey, Harrison, James W., Jeffries, Aaron R., Manley, Robin, Michell, Stephen L., Michelsen, Michelle L., Sambles, Christine M., Studholme, David J., Temperton, Ben, Warwick-Dugdale, Joanna, Darby, Alistair C., Eccles, Richard, Gemmell, Matthew, Gregory, Richard, Haldenby, Sam T., Hiscox, Julian A., Hughes, Margaret, Iturriza-Gomara, Miren, Jackson, Kathryn A., Lucaci, Anita O., Nelson, Charlotte, Paterson, Steve, Rainbow, Lucille, Turtle, Lance, Vamos, Edith E., Webster, Hermione J., Whitehead, Mark, Wierzbicki, Claudia, Angyal, Adrienn, Brown, Rebecca, de Silva, Thushan I., Freeman, Timothy M., Gallis, Marta, Green, Luke R., Groves, Danielle C., Keeley, Alexander J., Lindsey, Benjamin B., Louka, Stavroula F., Parker, Matthew D., Parsons, Paul J., Smith, Nikki, Tucker, Rachel M., Wang, Dennis, Whiteley, Max, Wyles, Matthew, Zhang, Peijun, Alam, Mohammad T., Baxter, Laura, Bridgewater, Hannah E., Brown, Paul E., Cheng, Jeffrey K. J., Constantinidou, Chrystala, Frost, Lucy R., Ott, Sascha, Stark, Richard, Taylor-Joyce, Grace, Unnikrishnan, Meera, Cerda, Alberto C., Merrill, Tammy V., Wilson, Rebekah E., Ball, Jonathan, Chappell, Joseph G., McClure, Patrick C., Tsoleridis, Theocharis, Buck, David, de Cesare, Mariateresa, Green, Angie, MacIntyre-Cockett, George, Todd, John A., Trebes, Amy, Gunson, Rory N., Cormie, Claire, Dias, Joana, Forrest, Sally, Gill, Harmeet K., Higginson, Ellen E., Kermack, Leanne M., Maes, Mailis, Ruis, Chris, Sridhar, Sushmita, Young, Jamie, Howes, Rob, McFarlane, Duncan, Dougan, Gordon, Pybus, Oliver G., Maxwell, Patrick H., Weekes, Michael P., Illingworth, Chris, Harrison, Ewan M., Matheson, Nicholas J., Goodfellow, Ian G., The Cambridge Covid-19 testing Centre, University of Cambridge Asymptomatic COVID-19 Screening Programm, The COVID-19 Genomics UK (COG-UK) Consortium, Aggarwal, Dinesh [0000-0002-5938-8172], Warne, Ben [0000-0003-1326-0373], Hill, Verity [0000-0002-3509-8146], Pinckert, Malte [0000-0002-6072-5949], Leek, Danielle [0000-0001-5367-3354], Pybus, Oliver [0000-0001-6619-6112], Weekes, Michael [0000-0002-0030-2784], Apollo - University of Cambridge Repository, Jahun, Aminu S [0000-0002-4585-1701], Hamilton, William L [0000-0002-3330-353X], du Plessis, Louis [0000-0003-0352-6289], Blane, Beth [0000-0002-0996-9091], Wright, Elizabeth [0000-0002-8378-9072], Hall, Grant [0000-0003-3928-3979], Chaudhry, Yasmin [0000-0002-2386-3269], Pinckert, Malte L [0000-0002-6072-5949], Izuagbe, Rhys [0000-0001-8080-2510], Nsonwu, Olisaeloka [0000-0002-3024-700X], Hughes, Gareth J [0000-0002-3781-0117], Packer, Simon [0000-0002-9157-3650], Page, Andrew J [0000-0001-6919-6062], Metaxaki, Marina [0000-0002-4552-1622], Weale, Gillian [0000-0003-4728-5915], Brown, Christopher A [0000-0001-7773-0878], Peacock, Sharon J [0000-0002-1718-2782], Pybus, Oliver G [0000-0002-8797-2667], Weekes, Michael P [0000-0003-3196-5545], Harrison, Ewan M [0000-0003-2720-0507], Matheson, Nicholas J [0000-0002-3318-1851], Goodfellow, Ian G [0000-0002-9483-510X], Jahun, Aminu [0000-0002-4585-1701], Hosmillo, Myra [0000-0002-3514-7681], McFarlane, Duncan [0000-0002-1558-7823], Dougan, Gordon [0000-0003-0022-965X], Peacock, Sharon [0000-0002-1718-2782], Weekes, Michael [0000-0003-3196-5545], Illingworth, Christopher [0000-0002-0030-2784], Harrison, Ewan [0000-0003-2720-0507], Matheson, Nicholas [0000-0002-3318-1851], and Goodfellow, Ian [0000-0002-9483-510X]

Subjects
Universities, 631/326/325/2483, Science, education, University of Cambridge Asymptomatic COVID-19 Screening Programme Consortium, General Physics and Astronomy, Cambridge Covid-19 testing Centre, 45/23, Genome, Viral, General Biochemistry, Genetics and Molecular Biology, COVID-19 Genomics UK (COG-UK) Consortium, Risk Factors, The COVID-19 Genomics UK (COG-UK) Consortium, Humans, Students, Phylogeny, 631/326/596/4130, Multidisciplinary, SARS-CoV-2, article, COVID-19, virus diseases, C500, General Chemistry, Genomics, C700, 692/700/478/174, United Kingdom, The Cambridge Covid-19 testing Centre, RNA, Viral, 631/326/596/2562, Contact Tracing, 631/326/596/2563
Abstract

Understanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics., Nature Communications, 13, ISSN:2041-1723

Published
2022

5. Recent trends and patterns in HIV‐1 transmitted drug resistance in the United Kingdom

Author

Tostevin, A, White, E, Dunn, D, Croxford, S, Delpech, V, Williams, I, Asboe, D, Pozniak, A, Churchill, D, Geretti, AM, Pillay, D, Sabin, C, LeighBrown, A, Smit, E, Aitken, Celia, Cane, Patricia, Chadwick, David, Clark, Duncan, Collins, Simon, Douthwaite, Samuel, Fearnhill, Esther, Porter, Kholoud, Fraser, Christophe, Hale, Antony, Hué, Stéphane, Kaye, Steve, Kellam, Paul, Lazarus, Linda, Mbisa, Tamyo, Mackie, Nicola, Moses, Samuel, Orkin, Chloe, Nastouli, Eleni, Phillips, Andrew, Templeton, Kate, Tilston, Peter, Zhang, Hongyi, Fairbrother, Keith, Greatorex, Jane, OʼShea, Siobhan, Mullen, Jane, Cox, Alison, Tandy, Richard, Fawcett, Tracy, Hopkins, Mark, Ashton, Lynne, Booth, Clare, GarciaDiaz, Ana, Shepherd, Jill, Schmid, Matthias L., Payne, Brendan, Pereira, Spiro, Hubb, Jonathan, Kirk, Stuart, Gunson, Rory, and BradleyStewart, Amanda

Published
2017
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9. Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial

Author

Todd, John A., Evangelou, Marina, Cutler, Antony J., Pekalski, Marcin L., Walker, Neil M., Stevens, Helen E., Porter, Linsey, Smyth, Deborah J., Rainbow, Daniel B., Ferreira, Ricardo C., Esposito, Laura, Hunter, Kara M. D., Loudon, Kevin, Irons, Kathryn, Yang, Jennie H., Bell, Charles J. M., Schuilenburg, Helen, Heywood, James, Challis, Ben, Neupane, Sankalpa, Clarke, Pamela, Coleman, Gillian, Dawson, Sarah, Goymer, Donna, Anselmiova, Katerina, Kennet, Jane, Brown, Judy, Caddy, Sarah L., Lu, Jia, Greatorex, Jane, Goodfellow, Ian, Wallace, Chris, Tree, Tim I., Evans, Mark, Mander, Adrian P., Bond, Simon, Wicker, Linda S., and Waldron-Lynch, Frank

Subjects
Immunotherapy -- Analysis -- Health aspects -- Research, Interleukin-2 -- Physiological aspects -- Genetic aspects -- Research, Type 1 diabetes -- Analysis -- Health aspects -- Genetic aspects -- Care and treatment -- Research, T cells -- Analysis -- Health aspects -- Physiological aspects -- Genetic aspects -- Research, Biological sciences
Abstract

Background Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4.sup.+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4.sup.+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. Methods and Findings To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3.sup.+ CD4.sup.+ CD25.sup.high CD127.sup.low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 x 10.sup.6 to 1.5 x 10.sup.6 IU/m.sup.2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 x 10.sup.6 IU/m.sup.2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 x 10.sup.6 IU/m.sup.2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 x 10.sup.6 and 0.045 x 10.sup.6 IU/m.sup.2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the [beta] chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. Conclusions The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D. Trial Registration ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735, Author(s): John A. Todd 1,*, Marina Evangelou 2, Antony J. Cutler 1, Marcin L. Pekalski 1, Neil M. Walker 1, Helen E. Stevens 1, Linsey Porter 1, Deborah J. Smyth [...]

Published
2016
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11. HIV seroprevalence, self-reported STIs and associated risk factors among men who have sex with men: a cross-sectional study in Rwanda, 2015

Author

Ntale, Roman Saba, Rutayisire, Gad, Mujyarugamba, Pierre, Shema, Eliah, Greatorex, Jane, Frost, Simon David William, and Kaleebu, Pontiano

Subjects
virus diseases
Abstract

OBJECTIVES: In many populations, men who have sex with men (MSM) are at a high risk of HIV infection. This study aimed to estimate the burden of HIV, other STIs and risk behaviours among Rwandan MSM. METHODS: In this cross-sectional study, we recruited through peer referral men aged between 18 and 60 years, who reported sex with men at least once in the 12 months prior to the survey. Representativeness was increased using 'seeds' from a variety of sources. Signed informed consent was obtained from all participants. Data on demographics, risk behaviours and self-reported STIs were collected through an interviewer-administered questionnaire. We screened all eligible participants for HIV using the Rwanda-approved protocol for rapid HIV detection. RESULTS: 504 MSM were recruited from five major cities in Rwanda. Participants were mostly young (median age 23 years, range 18-55 years) and unmarried (484/504, 96.0%). Thirteen per cent (65/504) of the participants reported past gonorrhoea and/or syphilis infection. Of 504 MSM, 53 (10.5%) reported they were diagnosed and treated for gonorrhoea in the past 12 months and 24 (4.8%) tested positive for HIV. A high proportion (232/504, 46%) reported receiving payment for sex by a man, with almost half of these reporting on more than three occasions (107/232, 46%). Many reported having had an HIV test within the past 12 months (385/504, 76.4%). In multivariate logistic regression models controlling for age, being paid for sex was associated with higher odds of past STI (OR 3.36 (1.82-6.43]; P

Published
2018

12. Virological failure and development of new resistance mutations according to CD4 count at combination antiretroviral therapy initiation

Author

Jose, S., Quinn, K., Dunn, D., Cox, A., Sabin, C., Fidler, S., Fisher, Martin, Gazzard, Brian, Gilson, Richard, Gompels, Mark, Hay, Phillip, Johnson, Margaret, Kegg, Stephen, Leen, C., Martin, Fabiola, Nelson, Mark, Palfreeman, Adrian, Post, F., Pritchard, Jillian, Sachikonye, Memory, Schwenk, Achim, Tariq, Anjum, Walsh, John, Hill, Teresa, Jose, Sophie, Phillips, Andrew, Sabin, Caroline, Thornton, Alicia, Dunn, David, Glabay, Adam, Fisher, M., Perry, N., Tilbury, S., Youssef, E., Churchill, D., Gazzard, B., Nelson, M., Everett, R., Asboe, D., Mandalia, S., Korat, H., Taylor, C., Gleisner, Z., Ibrahim, F., Campbell, L., Gilson, R., Brima, N., Williams, I., Johnson, M., Youle, M., Lampe, F., Smith, C., Tsintas, R., Chaloner, C., Hutchinson, S., Phillips, A., Hill, T., Thornton, A., Huntington, S., Walsh, J., Mackie, N., Winston, A., Weber, J., Ramzan, F., Carder, M., Orkin, C., Lynch, J., Hand, J., de Souza, C., Anderson, J., Munshi, S., Ainsworth, J., Schwenk, A., Miller, S., Wood, C., Wilson, A., Morris, S., Gompels, M., Allan, S., Palfreeman, A., Memon, K., Lewszuk, A., Chadwick, D., Cope, E., Gibson, J., Kegg, S., Main, P., Mitchell, Hunter, Hay, P., Dhillon, M., Martin, F., Russell-Sharpe, S., Harte, A., Clay, S., Tariq, A., Spencer, H., Jones, R., Pritchard, J., Cumming, S., Atkinson, C., Delpech, Valerie, Sachikony, M., Aitken, Celia, Asboe, David, Pozniak, Anton, Cane, Patricia, Chadwick, David, Churchill, Duncan, Clark, Duncan, Collins, Simon, Douthwaite, Samuel, Fearnhill, Esther, Porter, Kholoud, Tostevin, Anna, White, Ellen, Fraser, Christophe, Geretti, Anna Maria, Hale, Antony, Hué, Stéphane, Kaye, Steve, Kellam, Paul, Lazarus, Linda, Leigh-Brown, Andrew, Mbisa, Tamyo, Mackie, Nicola, Moses, Samuel, Orkin, Chloe, Nastouli, Eleni, Pillay, Deenan, Smit, Erasmus, Templeton, Kate, Tilston, Peter, Webster, Daniel, Williams, Ian, Zhang, Hongyi, Greatorex, Jane, O'Shea, Siobhan, Mullen, Jane, Cox, Alison, Tandy, Richard, Fawcett, Tracy, Hopkins, Mark, Ashton, Lynn, Booth, Claire, Garcia-Diaz, Ana, Shepherd, Jill, Schmid, Matthias L., Payne, Brendan, Pereira, Spiro, Hubb, Jonathan, Kirk, Stuart, Gunson, Rory, Bradley-Stewart, Amanda, and Medical Research Council (MRC)

Subjects
0301 basic medicine, Male, HAART, HIV Infections, Treatment failure, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Antiretroviral Therapy, Highly Active, Pharmacology (medical), 030212 general & internal medicine, Treatment Failure, virological failure, Health Policy, UK CHIC and UK HDRD Steering Committees, Virological failure, 3. Good health, Antiretroviral therapy, Patient benefit, Infectious Diseases, Female, medicine.symptom, Life Sciences & Biomedicine, Viral load, Cart, medicine.medical_specialty, Anti-HIV Agents, Short Communication, antiretroviral therapy, CD4 count, Asymptomatic, 03 medical and health sciences, HIV-INFECTION, Virology, Internal medicine, Drug Resistance, Viral, medicine, Humans, Science & Technology, business.industry, HIV resistance, 1103 Clinical Sciences, 030112 virology, CD4 Lymphocyte Count, Immunology, Mutation, business
Abstract

Objectives No randomized controlled trials have yet reported an individual patient benefit of initiating combination antiretroviral therapy (cART) at CD4 counts > 350 cells/μL. It is hypothesized that earlier initiation of cART in asymptomatic and otherwise healthy individuals may lead to poorer adherence and subsequently higher rates of resistance development. Methods In a large cohort of HIV-positive individuals, we investigated the emergence of new resistance mutations upon virological treatment failure according to the CD4 count at the initiation of cART. Results Of 7918 included individuals, 6514 (82.3%), 996 (12.6%) and 408 (5.2%) started cART with a CD4 count ≤ 350, 351–499 and ≥ 500 cells/μL, respectively. Virological rebound occurred while on cART in 488 (7.5%), 46 (4.6%) and 30 (7.4%) with a baseline CD4 count ≤ 350, 351–499 and ≥ 500 cells/μL, respectively. Only four (13.0%) individuals with a baseline CD4 count > 350 cells/μL in receipt of a resistance test at viral load rebound were found to have developed new resistance mutations. This compared to 107 (41.2%) of those with virological failure who had initiated cART with a CD4 count

Published
2015

13. Dimerisation of HIV-2 genomic RNA is linked to efficient RNA packaging, normal particle maturation and viral infectivity

Author

Crowther R Anthony, Greatorex Jane S, L'Hernault Anne, and Lever Andrew ML

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Background Retroviruses selectively encapsidate two copies of their genomic RNA, the Gag protein binding a specific RNA motif in the 5' UTR of the genome. In human immunodeficiency virus type 2 (HIV-2), the principal packaging signal (Psi) is upstream of the major splice donor and hence is present on all the viral RNA species. Cotranslational capture of the full length genome ensures specificity. HIV-2 RNA dimerisation is thought to occur at the dimer initiation site (DIS) located in stem-loop 1 (SL-1), downstream of the main packaging determinant. However, the HIV-2 packaging signal also contains a palindromic sequence (pal) involved in dimerisation. In this study, we analysed the role of the HIV-2 packaging signal in genomic RNA dimerisation in vivo and its implication in viral replication. Results Using a series of deletion and substitution mutants in SL-1 and the Psi region, we show that in fully infectious HIV-2, genomic RNA dimerisation is mediated by the palindrome pal. Mutation of the DIS had no effect on dimerisation or viral infectivity, while mutations in the packaging signal severely reduce both processes as well as RNA encapsidation. Electron micrographs of the Psi-deleted virions revealed a significant reduction in the proportion of mature particles and an increase in that of particles containing multiple cores. Conclusion In addition to its role in RNA encapsidation, the HIV-2 packaging signal contains a palindromic sequence that is critical for genomic RNA dimerisation. Encapsidation of a dimeric genome seems required for the production of infectious mature particles, and provides a promising therapeutic target.

Published
2007
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14. The retroviral RNA dimer linkage: different structures may reflect different roles

Author

Greatorex Jane

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Retroviruses are unique among virus families in having dimeric genomes. The RNA sequences and structures that link the two RNA molecules vary, and these differences provide clues as to the role of this feature in the viral lifecycles. This review draws upon examples from different retroviral families. Differences and similarities in both secondary and tertiary structure are discussed. The implication of varying roles for the dimer linkage in related viruses is considered.

Published
2004
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15. Identification and visualization of the dimerization initiation site of the prototype lentivirus, maedi visna virus: A potential GACG tetraloop displays structural homology with the alpha-and beta-retroviruses

Author

Monie, Tom P., Beales, Lucy P., Greatorex, Jane S., Lever, Andrew M.L., Maynard-Smith, Laura, Hook, Ben D.C., and Bishop, Naomi

Subjects
Retroviruses -- Research, Biological sciences, Chemistry
Abstract

Dimerization of retroviral genomic RNA is essential for efficient viral replication and is mediated by structural interactions between identical RNA motifs in the viral leader region. It is visualized, that by electron microscopy, RNA dimers formed from the leader region of the prototype lentivirus, maedi visna virus.

Published
2005

16. The human T-cell lymphotropic virus type-I dimerization initiation site forms a hairpin loop, unlike previously characterized retroviral dimerization motifs

Author

Monie, Tom P., Greatorex, Jane S., Zacharias, Martin, and Lever, Andrew M.L.

Subjects
Biochemistry -- Research, RNA -- Research, Lymphocytes -- Structure, Lymphocytes -- Research, Biological sciences, Chemistry
Abstract

The structural motif responsible for HTLV-I RNA dimerization forms a trinucleotide RNA loop, and is not like previously characterized retroviral dimerization motif. This is formed by an unusual C:synG base pair closing the loop, and indicates that such a motif also exist in other deltaretroviruses.

Published
2004

17. HIV seroprevalence, self-reported STIs and associated risk factors among men who have sex with men: a cross-sectional study in Rwanda, 2015.

Author

Ntale, Roman Saba, Rutayisire, Gad, Mujyarugamba, Pierre, Shema, Eliah, Greatorex, Jane, William Frost, Simon David, Kaleebu, Pontiano, and Frost, Simon David William

Subjects
SYPHILIS epidemiology, EPIDEMIOLOGY of sexually transmitted diseases, HIV infection epidemiology, COMPARATIVE studies, GONORRHEA, RESEARCH methodology, MEDICAL cooperation, RESEARCH, RESEARCH funding, RISK-taking behavior, SELF-evaluation, EVALUATION research, CROSS-sectional method, HIV seroconversion
Abstract

Objectives: In many populations, men who have sex with men (MSM) are at a high risk of HIV infection. This study aimed to estimate the burden of HIV, other STIs and risk behaviours among Rwandan MSM.Methods: In this cross-sectional study, we recruited through peer referral men aged between 18 and 60 years, who reported sex with men at least once in the 12 months prior to the survey. Representativeness was increased using 'seeds' from a variety of sources. Signed informed consent was obtained from all participants. Data on demographics, risk behaviours and self-reported STIs were collected through an interviewer-administered questionnaire. We screened all eligible participants for HIV using the Rwanda-approved protocol for rapid HIV detection.Results: 504 MSM were recruited from five major cities in Rwanda. Participants were mostly young (median age 23 years, range 18-55 years) and unmarried (484/504, 96.0%). Thirteen per cent (65/504) of the participants reported past gonorrhoea and/or syphilis infection. Of 504 MSM, 53 (10.5%) reported they were diagnosed and treated for gonorrhoea in the past 12 months and 24 (4.8%) tested positive for HIV. A high proportion (232/504, 46%) reported receiving payment for sex by a man, with almost half of these reporting on more than three occasions (107/232, 46%). Many reported having had an HIV test within the past 12 months (385/504, 76.4%). In multivariate logistic regression models controlling for age, being paid for sex was associated with higher odds of past STI (OR 3.36 (1.82-6.43]; P<0.001) and testing HIV positive (OR 3.13, P<0.05).Conclusion: Further research is needed to understand the high rate of payment for sex in this population, which appears to be a major risk factor for STI including HIV. [ABSTRACT FROM AUTHOR]

Published
2019
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18. Earlier detection of drug resistant mutations in small bowel/multivisceral transplant recipients with CMV infection using next generation sequencing

Author

Diao, Yanjun, primary, Greatorex, Jane, additional, Zhang, Hongyi, additional, English, Suzanne, additional, White, Heather, additional, Brugger, Kim, additional, Ambrose, Tim, additional, Butler, Andrew, additional, Russell, Neil, additional, Massey, Dunecan, additional, Middleton, Stephen, additional, and Gkrania-Klotsas, Effrossyni, additional

Published
2015
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21. Use of a Human Influenza Challenge Model to Assess Person-to-Person Transmission: Proof-of-Concept Study

Author

Killingley, Ben, primary, Enstone, Joanne E., additional, Greatorex, Jane, additional, Gilbert, Anthony S., additional, Lambkin-Williams, Rob, additional, Cauchemez, Simon, additional, Katz, Jacqueline M., additional, Booy, Robert, additional, Hayward, Andrew, additional, Oxford, John, additional, Bridges, Carolyn B., additional, Ferguson, Neil M., additional, and Nguyen Van-Tam, Jonathan S., additional

Published
2011
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31. Identification and Visualization of the Dimerization Initiation Site of the Prototype Lentivirus, Maedi Visna Virus: A Potential GACG Tetraloop Displays Structural Homology with the α and γ small gamma-Retroviruses.

Author

Monie, Tom P., Greatorex, Jane S., Maynard-Smith, Laura, Hook, Ben D. C., Bishop, Naomi, Beales, Lucy P., and Lever, Andrew M. L.

Subjects
*RNA, *GENOMICS, *LENTIVIRUSES, *RETROVIRUSES, *LEUKEMIA, *HOMOLOGY (Biology)
Abstract

Dimerization of retroviral genomic RNA is essential for efficient viral replication and is mediated by structural interactions between identical RNA motifs in the viral leader region. We have visualized, by electron microscopy, RNA dimers formed from the leader region of the prototype lentivirus, maedi visna virus. Characterization by in vitro assays of the domains responsible for this interaction has identified a 20 nucleotide sequence that functions as the core dimerization initiation site. This region is predicted to form a GACG tetraloop and therefore differs significantly from the kissing loop palindromes utilized to initiate dimerization in primate lentiviruses. The motif is strongly conserved across the ovine and caprine lentiviruses, implying a critical functional role. Furthermore, the proposed GACO tetraloop exhibits marked structural homology with similar structural motifs present in the leader regions of the α- and γ-retroviruses, and the maedi visna virus dimer linkage region is capable of forming heterodimeric species with the Moloney murine leukemia virus Ψ domain. This may be indicative of commonality of origin of the two viruses or convergent evolution. [ABSTRACT FROM AUTHOR]

Published
2005
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33. Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial

Author

Todd, John A, Evangelou, Marina, Cutler, Antony J, Pekalski, Marcin L, Walker, Neil M, Stevens, Helen E, Porter, Linsey, Smyth, Deborah J, Rainbow, Daniel B, Ferreira, Ricardo C, Esposito, Laura, Hunter, Kara MD, Loudon, Kevin, Irons, Kathryn, Yang, Jennie H, Bell, Charles JM, Schuilenburg, Helen, Heywood, James, Challis, Ben, Neupane, Sankalpa, Clarke, Pamela, Coleman, Gillian, Dawson, Sarah, Goymer, Donna, Anselmiova, Katerina, Kennet, Jane, Brown, Judy, Caddy, Sarah L, Lu, Jia, Greatorex, Jane, Goodfellow, Ian, Wallace, Chris, Tree, Tim I, Evans, Mark, Mander, Adrian P, Bond, Simon, Wicker, Linda S, and Waldron-Lynch, Frank

Subjects
Adult, Male, Adolescent, Dose-Response Relationship, Drug, Middle Aged, T-Lymphocytes, Regulatory, Recombinant Proteins, 3. Good health, Immunophenotyping, Eosinophils, Killer Cells, Natural, Young Adult, Diabetes Mellitus, Type 1, Humans, Interleukin-2, Female, Lymphocyte Count, Chemokines, Inflammation Mediators, Biomarkers
Abstract

BACKGROUND: Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. METHODS AND FINDINGS: To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the β chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. CONCLUSIONS: The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D. TRIAL REGISTRATION: ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735.

34. Low frequency of genotypic resistance in HIV-1-infected patients failing an atazanavir-containing regimen: a clinical cohort study

Author

Dolling, David I., Dunn, David T., Sutherland, Katherine A., Pillay, Deenan, Mbisa, Jean L., Parry, Chris M., Post, Frank A., Sabin, Caroline A., Cane, Patricia A., Aitken, Celia, Asboe, David, Webster, Daniel, Cane, Patricia, Castro, Hannah, Dunn, David, Dolling, David, Chadwick, David, Churchill, Duncan, Clark, Duncan, Collins, Simon, Delpech, Valerie, Geretti, Anna Maria, Goldberg, David, Hale, Antony, Hué, Stéphane, Kaye, Steve, Kellam, Paul, Lazarus, Linda, Leigh-Brown, Andrew, Mackie, Nicola, Orkin, Chloe, Rice, Philip, Phillips, Andrew, Sabin, Caroline, Smit, Erasmus, Templeton, Kate, Tilston, Peter, Tong, William, Williams, Ian, Zhang, Hongyi, Zuckerman, Mark, Greatorex, Jane, Wildfire, Adrian, O'Shea, Siobhan, Mullen, Jane, Mbisa, Tamyo, Cox, Alison, Tandy, Richard, Hale, Tony, Fawcett, Tracy, Hopkins, Mark, Ashton, Lynn, Booth, Claire, Garcia-Diaz, Ana, Shepherd, Jill, Schmid, Matthias L., Payne, Brendan, Hay, Phillip, Rice, Phillip, Paynter, Mary, Bibby, David, Kirk, Stuart, MacLean, Alasdair, Gunson, Rory, Coughlin, Kate, Fearnhill, Esther, Fradette, Lorraine, Porter, Kholoud, Ainsworth, Jonathan, Anderson, Jane, Babiker, Abdel, Fisher, Martin, Gazzard, Brian, Gilson, Richard, Gompels, Mark, Hill, Teresa, Johnson, Margaret, Kegg, Stephen, Leen, Clifford, Nelson, Mark, Palfreeman, Adrian, Post, Frank, Sachikonye, Memory, Schwenk, Achim, Walsh, John, Huntington, Susie, Jose, Sophie, Thornton, Alicia, Glabay, Adam, Orkin, C., Garrett, N., Lynch, J., Hand, J., de Souza, C., Fisher, M., Perry, N., Tilbury, S., Gazzard, B., Nelson, M., Waxman, M., Asboe, D., Mandalia, S., Delpech, V., Anderson, J., Munshi, S., Korat, H., Welch, J., Poulton, M., MacDonald, C., Gleisner, Z., Campbell, L., Gilson, R., Brima, N., Williams, I., Schwenk, A., Ainsworth, J., Wood, C., Miller, S., Johnson, M., Youle, M., Lampe, F., Smith, C., Grabowska, H., Chaloner, C., Puradiredja, D., Walsh, J., Weber, J., Ramzan, F., Mackie, N., Winston, A., Leen, C., Wilson, A., Allan, S., Palfreeman, A., Moore, A., and Wakeman, K.

Subjects
Male, Mutation rate, Pyridines, Human immunodeficiency virus (HIV), HIV Infections, medicine.disease_cause, THERAPY, Cohort Studies, 0302 clinical medicine, HIV Protease, Mutation Rate, 1108 Medical Microbiology, Genotype, Pharmacology (medical), 030212 general & internal medicine, Pharmacology & Pharmacy, Treatment Failure, drug resistance mutations, Original Research, 0303 health sciences, virological failure, UK Collaborative HIV Cohort Study (UK CHIC), Proteolytic enzymes, virus diseases, Middle Aged, 3. Good health, Infectious Diseases, Female, 1115 Pharmacology and Pharmaceutical Sciences, Life Sciences & Biomedicine, Oligopeptides, medicine.drug, Cohort study, 0605 Microbiology, Microbiology (medical), Adult, medicine.medical_specialty, Anti-HIV Agents, Atazanavir Sulfate, protease inhibitors, Mutation, Missense, RITONAVIR, Biology, Microbiology, Medication Adherence, 03 medical and health sciences, Internal medicine, SCORE, Drug Resistance, Viral, medicine, Humans, 030304 developmental biology, Pharmacology, Science & Technology, HIV, Virology, naive patients, United States, Atazanavir, Regimen, HIV-1, Ritonavir, UK HIV Drug Resistance Database (UKHDRD)
Abstract

Author(s): Dolling, David I; Dunn, David T; Sutherland, Katherine A; Pillay, Deenan; Mbisa, Jean L; Parry, Chris M; Post, Frank A; Sabin, Caroline A; Cane, Patricia A; UK HIV Drug Resistance Database (UKHDRD); UK Collaborative HIV Cohort Study (UK CHIC) | Abstract: ObjectivesTo determine protease mutations that develop at viral failure for protease inhibitor (PI)-naive patients on a regimen containing the PI atazanavir.MethodsResistance tests on patients failing atazanavir, conducted as part of routine clinical care in a multicentre observational study, were randomly matched by subtype to resistance tests from PI-naive controls to account for natural polymorphisms. Mutations from the consensus B sequence across the protease region were analysed for association and defined using the IAS-USA 2011 classification list.ResultsFour hundred and five of 2528 (16%) patients failed therapy containing atazanavir as a first PI over a median (IQR) follow-up of 1.76 (0.84-3.15) years and 322 resistance tests were available for analysis. Recognized major atazanavir mutations were found in six atazanavir-experienced patients (P l 0.001), including I50L and N88S. The minor mutations most strongly associated with atazanavir experience were M36I, M46I, F53L, A71V, V82T and I85V (P l 0.05). Multiple novel mutations, I15S, L19T, K43T, L63P/V, K70Q, V77I and L89I/T/V, were also associated with atazanavir experience.ConclusionsViral failure on atazanavir-containing regimens was not common and major resistance mutations were rare, suggesting that adherence may be a major contributor to viral failure. Novel mutations were described that have not been previously documented.

35. Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial

Author

Todd, John A, Evangelou, Marina, Cutler, Antony J, Pekalski, Marcin L, Walker, Neil M, Stevens, Helen E, Porter, Linsey, Smyth, Deborah J, Rainbow, Daniel B, Ferreira, Ricardo C, Esposito, Laura, Hunter, Kara MD, Loudon, Kevin, Irons, Kathryn, Yang, Jennie H, Bell, Charles JM, Schuilenburg, Helen, Heywood, James, Challis, Ben, Neupane, Sankalpa, Clarke, Pamela, Coleman, Gillian, Dawson, Sarah, Goymer, Donna, Anselmiova, Katerina, Kennet, Jane, Brown, Judy, Caddy, Sarah, Lu, Jia, Greatorex, Jane, Goodfellow, Ian Gordon, Wallace, Chris, Tree, Tim I, Evans, Mark, Mander, Adrian Paul, Bond, Simon, Wicker, Linda S, and Waldron-Lynch, Frank

Subjects
lymphocytes, blood counts, blood, memory T cells, T cells, eosinophils, regulatory T cells, 3. Good health, blood plasma
Abstract

BACKGROUND: Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. METHODS AND FINDINGS: To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the β chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. CONCLUSIONS: The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D. TRIAL REGISTRATION: ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735., This is the final version of the article. It first appeared from the Public Library of Science via http://dx.doi.org/10.1371/journal.pmed.1002139

36. Low-Density TaqMan® Array Cards for the Detection of Pathogens.

Author

Heaney J, Rolfe K, Gleadall NS, Greatorex JS, and Curran MD

Abstract

Real-time PCR assays have revolutionised diagnostic microbiology over the past 15 years or more. Adaptations and improvements over that time frame have led to the development of multiplex assays. However, limitations in terms of available fluorophores has meant the number of assays which can be combined has remained in single figures. This latter limitation has led to the focus tending to be on individual pathogens and their detection. This chapter describes the development of TaqMan® Array Cards (TACs), technology which allows the detection of multiple pathogens (up to 48 targets) from a single nucleic acid extract, utilising small volumes and real-time PCR. This in turn lends itself to a syndromic approach to infectious disease diagnosis. Using the examples of TACs we have developed in our own laboratory, as well as others, we explain the design, optimisation and use of TACs for respiratory, gastrointestinal and liver infections. Refinement of individual assays is discussed as well as the incorporation of appropriate internal and process controls onto the array cards. Finally, specific examples are given of instances where the assays have had a direct, positive impact on patient care., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Published
2015
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