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1. Africa-specific human genetic variation near CHD1L associates with HIV-1 load

Author

McLaren, Paul J., Porreca, Immacolata, Iaconis, Gennaro, Mok, Hoi Ping, Mukhopadhyay, Subhankar, Karakoc, Emre, Cristinelli, Sara, Pomilla, Cristina, Bartha, István, Thorball, Christian W., Tough, Riley H., Angelino, Paolo, Kiar, Cher S., Carstensen, Tommy, Fatumo, Segun, Porter, Tarryn, Jarvis, Isobel, Skarnes, William C., Bassett, Andrew, DeGorter, Marianne K., Sathya Moorthy, Mohana Prasad, Tuff, Jeffrey F., Kim, Eun-Young, Walter, Miriam, Simons, Lacy M., Bashirova, Arman, Buchbinder, Susan, Carrington, Mary, Cossarizza, Andrea, De Luca, Andrea, Goedert, James J., Goldstein, David B., Haas, David W., Herbeck, Joshua T., Johnson, Eric O., Kaleebu, Pontiano, Kilembe, William, Kirk, Gregory D., Kootstra, Neeltje A., Kral, Alex H., Lambotte, Olivier, Luo, Ma, Mallal, Simon, Martinez-Picado, Javier, Meyer, Laurence, Miro, José M., Moodley, Pravi, Motala, Ayesha A., Mullins, James I., Nam, Kireem, Obel, Niels, Pirie, Fraser, Plummer, Francis A., Poli, Guido, Price, Matthew A., Rauch, Andri, Theodorou, Ioannis, Trkola, Alexandra, Walker, Bruce D., Winkler, Cheryl A., Zagury, Jean-François, Montgomery, Stephen B., Ciuffi, Angela, Hultquist, Judd F., Wolinsky, Steven M., Dougan, Gordon, Lever, Andrew M. L., Gurdasani, Deepti, Groom, Harriet, Sandhu, Manjinder S., and Fellay, Jacques

Published
2023
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2. A high-resolution HLA reference panel capturing global population diversity enables multi-ancestry fine-mapping in HIV host response

Author

Luo, Yang, Kanai, Masahiro, Choi, Wanson, Li, Xinyi, Sakaue, Saori, Yamamoto, Kenichi, Ogawa, Kotaro, Gutierrez-Arcelus, Maria, Gregersen, Peter K, Stuart, Philip E, Elder, James T, Forer, Lukas, Schönherr, Sebastian, Fuchsberger, Christian, Smith, Albert V, Fellay, Jacques, Carrington, Mary, Haas, David W, Guo, Xiuqing, Palmer, Nicholette D, Chen, Yii-Der Ida, Rotter, Jerome I, Taylor, Kent D, Rich, Stephen S, Correa, Adolfo, Wilson, James G, Kathiresan, Sekar, Cho, Michael H, Metspalu, Andres, Esko, Tonu, Okada, Yukinori, Han, Buhm, McLaren, Paul J, and Raychaudhuri, Soumya

Subjects
Biological Sciences, Genetics, Biotechnology, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Alleles, Amino Acids, Gene Frequency, Genetic Variation, Genetics, Population, HIV Infections, HIV-1, HLA Antigens, Haplotypes, Host-Pathogen Interactions, Humans, Linkage Disequilibrium, Physical Chromosome Mapping, Reference Standards, Selection, Genetic, Viral Load, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Fine-mapping to plausible causal variation may be more effective in multi-ancestry cohorts, particularly in the MHC, which has population-specific structure. To enable such studies, we constructed a large (n = 21,546) HLA reference panel spanning five global populations based on whole-genome sequences. Despite population-specific long-range haplotypes, we demonstrated accurate imputation at G-group resolution (94.2%, 93.7%, 97.8% and 93.7% in admixed African (AA), East Asian (EAS), European (EUR) and Latino (LAT) populations). Applying HLA imputation to genome-wide association study data for HIV-1 viral load in three populations (EUR, AA and LAT), we obviated effects of previously reported associations from population-specific HIV studies and discovered a novel association at position 156 in HLA-B. We pinpointed the MHC association to three amino acid positions (97, 67 and 156) marking three consecutive pockets (C, B and D) within the HLA-B peptide-binding groove, explaining 12.9% of trait variance.

Published
2021

4. Author Correction: Africa-specific human genetic variation near CHD1L associates with HIV-1 load

Author

McLaren, Paul J., Porreca, Immacolata, Iaconis, Gennaro, Mok, Hoi Ping, Mukhopadhyay, Subhankar, Karakoc, Emre, Cristinelli, Sara, Pomilla, Cristina, Bartha, István, Thorball, Christian W., Tough, Riley H., Angelino, Paolo, Kiar, Cher S., Carstensen, Tommy, Fatumo, Segun, Porter, Tarryn, Jarvis, Isobel, Skarnes, William C., Bassett, Andrew, DeGorter, Marianne K., Sathya Moorthy, Mohana Prasad, Tuff, Jeffrey F., Kim, Eun-Young, Walter, Miriam, Simons, Lacy M., Bashirova, Arman, Buchbinder, Susan, Carrington, Mary, Cossarizza, Andrea, De Luca, Andrea, Goedert, James J., Goldstein, David B., Haas, David W., Herbeck, Joshua T., Johnson, Eric O., Kaleebu, Pontiano, Kilembe, William, Kirk, Gregory D., Kootstra, Neeltje A., Kral, Alex H., Lambotte, Olivier, Luo, Ma, Mallal, Simon, Martinez-Picado, Javier, Meyer, Laurence, Miro, José M., Moodley, Pravi, Motala, Ayesha A., Mullins, James I., Nam, Kireem, Obel, Niels, Pirie, Fraser, Plummer, Francis A., Poli, Guido, Price, Matthew A., Rauch, Andri, Theodorou, Ioannis, Trkola, Alexandra, Walker, Bruce D., Winkler, Cheryl A., Zagury, Jean-François, Montgomery, Stephen B., Ciuffi, Angela, Hultquist, Judd F., Wolinsky, Steven M., Dougan, Gordon, Lever, Andrew M. L., Gurdasani, Deepti, Groom, Harriet, Sandhu, Manjinder S., and Fellay, Jacques

Published
2023
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5. CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome

Author

Kulkarni, Smita, Lied, Alexandra, Kulkarni, Viraj, Rucevic, Marijana, Martin, Maureen P, Walker-Sperling, Victoria, Anderson, Stephen K, Ewy, Rodger, Singh, Sukhvinder, Nguyen, Hoang, McLaren, Paul J, Viard, Mathias, Naranbhai, Vivek, Zou, Chengcheng, Lin, Zhansong, Gatanaga, Hiroyuki, Oka, Shinichi, Takiguchi, Masafumi, Thio, Chloe L, Margolick, Joseph, Kirk, Gregory D, Goedert, James J, Hoots, W Keith, Deeks, Steven G, Haas, David W, Michael, Nelson, Walker, Bruce, Le Gall, Sylvie, Chowdhury, Fatema Z, Yu, Xu G, and Carrington, Mary

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Sexually Transmitted Infections, Genetics, Human Genome, Infectious Diseases, HIV/AIDS, 2.1 Biological and endogenous factors, Infection, Good Health and Well Being, 3' Untranslated Regions, Alleles, Biomarkers, CD4-Positive T-Lymphocytes, Cell Membrane, Gene Expression Regulation, Genes, Reporter, Genetic Variation, Genotype, HIV Infections, HIV-1, Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Population Groups, Prognosis, RNA Stability, RNA, Antisense, RNA, Long Noncoding, RNA, Messenger, Receptors, CCR5, Viral Load, Biochemistry and cell biology
Abstract

Multiple genome-wide studies have identified associations between outcome of human immunodeficiency virus (HIV) infection and polymorphisms in and around the gene encoding the HIV co-receptor CCR5, but the functional basis for the strongest of these associations, rs1015164A/G, is unknown. We found that rs1015164 marks variation in an activating transcription factor 1 binding site that controls expression of the antisense long noncoding RNA (lncRNA) CCR5AS. Knockdown or enhancement of CCR5AS expression resulted in a corresponding change in CCR5 expression on CD4+ T cells. CCR5AS interfered with interactions between the RNA-binding protein Raly and the CCR5 3' untranslated region, protecting CCR5 messenger RNA from Raly-mediated degradation. Reduction in CCR5 expression through inhibition of CCR5AS diminished infection of CD4+ T cells with CCR5-tropic HIV in vitro. These data represent a rare determination of the functional importance of a genome-wide disease association where expression of a lncRNA affects HIV infection and disease progression.

Published
2019

6. Author Correction: Increased prevalence of clonal hematopoiesis of indeterminate potential amongst people living with HIV

Author

Bick, Alexander G., Popadin, Konstantin, Thorball, Christian W., Uddin, Md Mesbah, Zanni, Markella V., Yu, Bing, Cavassini, Matthias, Rauch, Andri, Tarr, Philip, Schmid, Patrick, Bernasconi, Enos, Günthard, Huldrych F., Libby, Peter, Boerwinkle, Eric, McLaren, Paul J., Ballantyne, Christie M., Grinspoon, Steven, Natarajan, Pradeep, and Fellay, Jacques

Published
2022
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7. Increased prevalence of clonal hematopoiesis of indeterminate potential amongst people living with HIV

Author

Bick, Alexander G., Popadin, Konstantin, Thorball, Christian W., Uddin, Md Mesbah, Zanni, Markella V., Yu, Bing, Cavassini, Matthias, Rauch, Andri, Tarr, Philip, Schmid, Patrick, Bernasconi, Enos, Günthard, Huldrych F., Libby, Peter, Boerwinkle, Eric, McLaren, Paul J., Ballantyne, Christie M., Grinspoon, Steven, Natarajan, Pradeep, and Fellay, Jacques

Published
2022
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9. Exome Sequencing of a Blastomycosis Case–Control Cohort From Manitoba and Northwestern Ontario, Canada.

Author

Jankowski, Paul, Lee, Emma R., Embil, John, Keynan, Yoav, and McLaren, Paul J.

Subjects
DISEASE risk factors, FALSE discovery rate, BLASTOMYCOSIS, DISEASE susceptibility, GENETIC variation
Abstract

Background: Blastomycosis is a pulmonary disease caused by Blastomyces spp., a group of pathogenic dimorphic fungi endemic to a number of geographic regions, specifically Manitoba and northwestern Ontario, Canada. Immunosuppression is a major risk factor affecting disease susceptibility, yet host immunity is not well understood. Genetic immunodeficiencies can also influence disease, with variants in IL6, GATA2 and VDBP shown to influence susceptibility. Additional genetic factors in disease susceptibility and severity remain undetected. Our study seeks to identify potential genetic risk factors in a blastomycosis case–control cohort from Manitoba and northwestern Ontario, Canada. Methods: Exomes from 18 blastomycosis cases and 9 controls were sequenced, variants were identified and filtered for accuracy and quality. We performed candidate gene prioritisation and variant aggregation to identify genetic associations and explored the full exome dataset. Results: Ninety‐nine genetic variants in 42 candidate genes were identified in the exome dataset. No variants associated with susceptibility were identified in a single‐variant analysis although two non‐synonymous variants in TYK2 were enriched among cases suggesting a possible role in susceptibility. Gene‐based association analysis found variants in TLR1 enriched in controls (p = 0.024) suggesting a possible protective effect. Gene cluster analysis identified genetic variants in genes of chromatin remodelling, proteasome and intraflagellar transport significantly enriched in cases (false discovery rates < 14%). Conclusions: The findings in this study show novel associations with blastomycosis susceptibility. A better understanding of host immunity and genetic predisposition to Blastomyces infection can help to inform clinical practice for improved outcomes. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Host genetic predictors of the kynurenine pathway of tryptophan catabolism among treated HIV-infected Ugandans

Author

Lee, Sulggi A, Mefford, Joel A, Huang, Yong, Witte, John S, Martin, Jeffrey N, Haas, David W, Mclaren, Paul J, Mushiroda, Taisei, Kubo, Michiaki, Byakwaga, Helen, Hunt, Peter W, and Kroetz, Deanna L

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Human Genome, Clinical Research, Genetics, Sexually Transmitted Infections, HIV/AIDS, Infectious Diseases, Aetiology, 2.1 Biological and endogenous factors, Infection, Good Health and Well Being, Adult, Anti-Retroviral Agents, Female, HIV Infections, Humans, Indoleamine-Pyrrole 2, 3, -Dioxygenase, Interferon-gamma, Kynurenine, Male, Metabolism, Plasma, Risk Assessment, Signal Transduction, Survival Analysis, Toll-Like Receptors, Tryptophan, Tumor Necrosis Factor-alpha, Uganda, antiretroviral therapy, genome-wide association study, HIV, kynurenine, tryptophan, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Virology, Biomedical and clinical sciences, Health sciences
Abstract

ObjectivePlasma kynurenine/tryptophan ratio, a biomarker of indoleamine 2,3-dioxygenase-1 (IDO) activity, is a strong independent predictor of mortality in HIV-infected Ugandans initiating antiretroviral therapy (ART) and may play a key role in HIV pathogenesis. We performed a genome-wide study to identify potential host genetic determinants of kynurenine/tryptophan ratio in HIV-infected ART-suppressed Ugandans.Design/methodsWe performed genome-wide and exome array genotyping and measured plasma kynurenine/tryptophan ratio during the initial 6-12 months of suppressive ART in Ugandans. We evaluated more than 16 million single nucleotide polymorphisms in association with log10 kynurenine/tryptophan ratio using linear mixed models adjusted for cohort, sex, pregnancy, and ancestry.ResultsAmong 597 Ugandans, 62% were woman, median age was 35, median baseline CD4 cell count was 135 cells/μl, and median baseline HIV-1 RNA was 5.1 log10 copies/ml. Several polymorphisms in candidate genes TNF, IFNGR1, and TLR4 were associated with log10 kynurenine/tryptophan ratio (P

Published
2016

12. The HLA-B*57:01 allele corresponds to a very large MHC haploblock likely explaining its massive effect for HIV-1 elite control

Author

Rahmouni, Myriam, primary, De Marco, Lorenzo, additional, Spadoni, Jean-Louis, additional, Tison, Maxime, additional, Medina-Santos, Raissa, additional, Labib, Taoufik, additional, Noirel, Josselin, additional, Tamouza, Ryad, additional, Limou, Sophie, additional, Delaneau, Olivier, additional, Fellay, Jacques, additional, Bensussan, Armand, additional, Le Clerc, Sigrid, additional, McLaren, Paul J., additional, and Zagury, Jean-François, additional

Published
2023
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13. Transcriptomics and chromatin accessibility in multiple African population samples

Author

DeGorter, Marianne K, primary, Goddard, Page C, additional, Karakoc, Emre, additional, Kundu, Soumya, additional, Yan, Stephanie M, additional, Nachun, Daniel, additional, Abell, Nathan, additional, Aguirre, Matthew, additional, Carstensen, Tommy, additional, Chen, Ziwei, additional, Durrant, Matthew, additional, Dwaracherla, Vikranth R, additional, Feng, Karen, additional, Gloudemans, Michael J, additional, Hunter, Naiomi, additional, Moorthy, Mohana P S, additional, Pomilla, Cristina, additional, Rodrigues, Kameron B, additional, Smith, Courtney J, additional, Smith, Kevin S, additional, Ungar, Rachel A, additional, Balliu, Brunilda, additional, Fellay, Jacques, additional, Flicek, Paul, additional, McLaren, Paul J, additional, Henn, Brenna, additional, McCoy, Rajiv C, additional, Sugden, Lauren, additional, Kundaje, Anshul, additional, Sandhu, Manjinder S, additional, Gurdasani, Deepti, additional, and Montgomery, Stephen B, additional

Published
2023
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16. Host genetic variation at a locus near CHD1L impacts HIV sequence diversity in a South African population

Author

Schulz, Vanessa E., primary, Tuff, Jeffrey F., additional, Tough, Riley H., additional, Lewis, Lara, additional, Chimukangara, Benjamin, additional, Garrett, Nigel, additional, Abdool Karim, Quarraisha, additional, Abdool Karim, Salim S., additional, McKinnon, Lyle R., additional, Kharsany, Ayesha B. M., additional, and McLaren, Paul J., additional

Published
2023
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17. Rectal microbiota diversity in Kenyan men who have sex with men (MSM) is inversely associated with frequency of receptive anal sex, independent of HIV status

Author

Gebrebrhan, Henok, Kambaran, Cheli, Sivro, Aida, Adhiambo, Wendy, Siele, Naomi, Becker, Michael G., Li, Jie, Choi, Sandra, Mwatelah, Ruth S., Reyes, N. Vincent, Akolo, Maureen, Njogu, Peter, Cholette, François, Ho, John, Kim, John, Peterson, Shelley W., Martin, Irene, Sandstrom, Paul, Mehta, Supriya D., Lorway, Robert R., Ball, T. Blake, Kimani, Joshua, Mclaren, Paul J., Ji, Hezhao, and Mckinnon, Lyle R.

Published
2021
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18. Evaluating the Impact of Functional Genetic Variation on HIV-1 Control

Author

McLaren, Paul J., Pulit, Sara L., Gurdasani, Deepti, Bartha, Istvan, Shea, Patrick R., Pomilla, Cristina, Gupta, Namrata, Gkrania-Klotsas, Effrossyni, Young, Elizabeth H., Bannert, Norbert, Del Amo, Julia, Gill, M John, Gilmour, Jill, Kellam, Paul, Kelleher, Anthony D., Sönnerborg, Anders, Zangerle, Robert, Post, Frank A., Fisher, Martin, Haas, David W., Walker, Bruce D., Porter, Kholoud, Goldstein, David B., Sandhu, Manjinder S., de Bakker, Paul I.W., and Fellay, Jacques

Published
2017

19. Fine-mapping classical HLA variation associated with durable host control of HIV-1 infection in African Americans

Author

McLaren, Paul J, Ripke, Stephan, Pelak, Kimberly, Weintrob, Amy C, Patsopoulos, Nikolaos A, Jia, Xiaoming, Erlich, Rachel L, Lennon, Niall J, Kadie, Carl M, Heckerman, David, Gupta, Namrata, Haas, David W, Deeks, Steven G, Pereyra, Florencia, Walker, Bruce D, and de Bakker, Paul IW

Subjects
Biological Sciences, Genetics, Minority Health, HIV/AIDS, Sexually Transmitted Infections, Clinical Research, Infectious Diseases, Aetiology, 2.1 Biological and endogenous factors, Infection, Black or African American, Disease Resistance, Genetic Variation, HIV Infections, HIV-1, HLA Antigens, HLA-B Antigens, Humans, Polymorphism, Single Nucleotide, International HIV Controllers Study, Medical and Health Sciences, Genetics & Heredity
Abstract

A small proportion of human immunodeficiency virus-1 (HIV-1) infected individuals, termed HIV-1 controllers, suppress viral replication to very low levels in the absence of therapy. Genetic investigations of this phenotype have strongly implicated variation in the class I major histocompatibility complex (MHC) region as key to HIV-1 control. We collected sequence-based classical class I HLA genotypes at 4-digit resolution in HIV-1-infected African American controllers and progressors (n = 1107), and tested them for association with host control using genome-wide single nucleotide polymorphism data to account for population structure. Several classical alleles at HLA-B were associated with host control, including B*57:03 [odds ratio (OR) = 5.1; P= 3.4 × 10(-18)] and B*81:01 (OR = 4.8; P= 1.3 × 10(-9)). Analysis of variable amino acid positions demonstrates that HLA-B position 97 is the most significant association with host control in African Americans (omnibus P = 1.2 × 10(-21)) and explains the signal of several HLA-B alleles, including B*57:03. Within HLA-B, we also identified independent effects at position 116 (omnibus P= 2.8 × 10(-15)) in the canonical F pocket, position 63 in the B pocket (P= 1.5 × 10(-3)) and the non-pocket position 245 (P= 8.8 × 10(-10)), which is thought to influence CD8-binding kinetics. Adjusting for these HLA-B effects, there is evidence for residual association in the MHC region. These results underscore the key role of HLA-B in affecting HIV-1 replication, likely through the molecular interaction between HLA-B and viral peptides presented by infected cells, and suggest that sites outside the peptide-binding pocket also influence HIV-1 control.

Published
2012

20. Author Correction: A high-resolution HLA reference panel capturing global population diversity enables multi-ancestry fine-mapping in HIV host response

Author

Luo, Yang, Kanai, Masahiro, Choi, Wanson, Li, Xinyi, Sakaue, Saori, Yamamoto, Kenichi, Ogawa, Kotaro, Gutierrez-Arcelus, Maria, Gregersen, Peter K., Stuart, Philip E., Elder, James T., Forer, Lukas, Schönherr, Sebastian, Fuchsberger, Christian, Smith, Albert V., Fellay, Jacques, Carrington, Mary, Haas, David W., Guo, Xiuqing, Palmer, Nicholette D., Chen, Yii-Der Ida, Rotter, Jerome I., Taylor, Kent D., Rich, Stephen S., Correa, Adolfo, Wilson, James G., Kathiresan, Sekar, Cho, Michael H., Metspalu, Andres, Esko, Tonu, Okada, Yukinori, Han, Buhm, McLaren, Paul J., and Raychaudhuri, Soumya

Published
2021
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21. Severe viral respiratory infections in children with IFIH1 loss-of-function mutations

Author

Asgari, Samira, Schlapbach, Luregn J., Anchisi, Stéphanie, Hammer, Christian, Bartha, Istvan, Junier, Thomas, Mottet-Osman, Geneviève, Posfay-Barbe, Klara M., Longchamp, David, Stocker, Martin, Cordey, Samuel, Kaiser, Laurent, Riedel, Thomas, Kenna, Tony, Long, Deborah, Schibler, Andreas, Telenti, Amalio, Tapparel, Caroline, McLaren, Paul J., Garcin, Dominique, and Fellay, Jacques

Published
2017

25. Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load

Author

McLaren, Paul J., Coulonges, Cedric, Bartha, István, Lenz, Tobias L., Deutsch, Aaron J., Bashirova, Arman, Buchbinder, Susan, Carrington, Mary N., Cossarizza, Andrea, Dalmau, Judith, De Luca, Andrea, Goedert, James J., Gurdasani, Deepti, Haas, David W., Herbeck, Joshua T., Johnson, Eric O., Kirk, Gregory D., Lambotte, Olivier, Luo, Ma, Mallal, Simon, van Manen, Daniëlle, Martinez-Picado, Javier, Meyer, Laurence, Miro, José M., Mullins, James I., Obel, Niels, Poli, Guido, Sandhu, Manjinder S., Schuitemaker, Hanneke, Shea, Patrick R., Theodorou, Ioannis, Walker, Bruce D., Weintrob, Amy C., Winkler, Cheryl A., Wolinsky, Steven M., Raychaudhuri, Soumya, Goldstein, David B., Telenti, Amalio, de Bakker, Paul I. W., Zagury, Jean-François, and Fellay, Jacques

Published
2015

26. Community Insights in Phylogenetic HIV Research: The CIPHR Project Protocol

Author

Cholette, François, primary, Lazarus, Lisa, additional, Macharia, Pascal, additional, Thompson, Laura H., additional, Githaiga, Samuel, additional, Mathenge, John, additional, Walimbwa, Jeffrey, additional, Kuria, Irene, additional, Okoth, Silvia, additional, Wambua, Solomon, additional, Albert, Harrison, additional, Mwangi, Peninah, additional, Adhiambo, Joyce, additional, Kasiba, Rosemary, additional, Juma, Esther, additional, Battacharjee, Parinita, additional, Kimani, Joshua, additional, Sandstrom, Paul, additional, Meyers, Adrienne F. A., additional, Joy, Jeffrey B., additional, Thomann, Matthew, additional, McLaren, Paul J., additional, Shaw, Souradet, additional, Mishra, Sharmistha, additional, Becker, Marissa L., additional, McKinnon, Lyle, additional, and Lorway, Robert, additional

Published
2023
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27. Author Correction: CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome

Author

Kulkarni, Smita, Lied, Alexandra, Kulkarni, Viraj, Rucevic, Marijana, Martin, Maureen P., Walker-Sperling, Victoria, Anderson, Stephen K., Ewy, Rodger, Singh, Sukhvinder, Nguyen, Hoang, McLaren, Paul J., Viard, Mathias, Naranbhai, Vivek, Zou, Chengcheng, Lin, Zhansong, Gatanaga, Hiroyuki, Oka, Shinichi, Takiguchi, Masafumi, Thio, Chloe L., Margolick, Joseph, Kirk, Gregory D., Goedert, James J., Hoots, W. Keith, Deeks, Steven G., Haas, David W., Michael, Nelson, Walker, Bruce, Le Gall, Sylvie, Chowdhury, Fatema Z., Yu, Xu G., and Carrington, Mary

Published
2019
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30. Africa-specific human genetic variation near CHD1Lassociates with HIV-1 load

Author

McLaren, Paul J., Porreca, Immacolata, Iaconis, Gennaro, Mok, Hoi Ping, Mukhopadhyay, Subhankar, Karakoc, Emre, Cristinelli, Sara, Pomilla, Cristina, Bartha, István, Thorball, Christian W., Tough, Riley H., Angelino, Paolo, Kiar, Cher S., Carstensen, Tommy, Fatumo, Segun, Porter, Tarryn, Jarvis, Isobel, Skarnes, William C., Bassett, Andrew, DeGorter, Marianne K., Sathya Moorthy, Mohana Prasad, Tuff, Jeffrey F., Kim, Eun-Young, Walter, Miriam, Simons, Lacy M., Bashirova, Arman, Buchbinder, Susan, Carrington, Mary, Cossarizza, Andrea, De Luca, Andrea, Goedert, James J., Goldstein, David B., Haas, David W., Herbeck, Joshua T., Johnson, Eric O., Kaleebu, Pontiano, Kilembe, William, Kirk, Gregory D., Kootstra, Neeltje A., Kral, Alex H., Lambotte, Olivier, Luo, Ma, Mallal, Simon, Martinez-Picado, Javier, Meyer, Laurence, Miro, José M., Moodley, Pravi, Motala, Ayesha A., Mullins, James I., Nam, Kireem, Obel, Niels, Pirie, Fraser, Plummer, Francis A., Poli, Guido, Price, Matthew A., Rauch, Andri, Theodorou, Ioannis, Trkola, Alexandra, Walker, Bruce D., Winkler, Cheryl A., Zagury, Jean-François, Montgomery, Stephen B., Ciuffi, Angela, Hultquist, Judd F., Wolinsky, Steven M., Dougan, Gordon, Lever, Andrew M. L., Gurdasani, Deepti, Groom, Harriet, Sandhu, Manjinder S., and Fellay, Jacques

Abstract

HIV-1 remains a global health crisis1, highlighting the need to identify new targets for therapies. Here, given the disproportionate HIV-1 burden and marked human genome diversity in Africa2, we assessed the genetic determinants of control of set-point viral load in 3,879 people of African ancestries living with HIV-1 participating in the international collaboration for the genomics of HIV3. We identify a previously undescribed association signal on chromosome 1 where the peak variant associates with an approximately 0.3 log10-transformed copies per ml lower set-point viral load per minor allele copy and is specific to populations of African descent. The top associated variant is intergenic and lies between a long intergenic non-coding RNA (LINC00624) and the coding gene CHD1L, which encodes a helicase that is involved in DNA repair4. Infection assays in iPS cell-derived macrophages and other immortalized cell lines showed increased HIV-1 replication in CHD1L-knockdown and CHD1L-knockout cells. We provide evidence from population genetic studies that Africa-specific genetic variation near CHD1Lassociates with HIV replication in vivo. Although experimental studies suggest that CHD1L is able to limit HIV infection in some cell types in vitro, further investigation is required to understand the mechanisms underlying our observations, including any potential indirect effects of CHD1L on HIV spread in vivo that our cell-based assays cannot recapitulate.

Published
2023
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33. Increased prevalence of clonal hematopoiesis of indeterminate potential amongst people living with HIV

Author

Bick, Alexander G, Popadin, Konstantin, Thorball, Christian W, Uddin, Md Mesbah, Zanni, Markella V, Yu, Bing, Cavassini, Matthias, Rauch, Andri, Tarr, Philip, Schmid, Patrick, Bernasconi, Enos, G��nthard, Huldrych F, Libby, Peter, Boerwinkle, Eric, McLaren, Paul J, Ballantyne, Christie M, Grinspoon, Steven, Natarajan, Pradeep, Fellay, Jacques, Swiss HIV Cohort Study, Abela, I., Aebi-Popp, K., Anagnostopoulos, A., Battegay, M., Bernasconi, E., Braun, D.L., Bucher, H.C., Calmy, A., Cavassini, M., Ciuffi, A., Dollenmaier, G., Egger, M., Elzi, L., Fehr, J., Fellay, J., Furrer, H., Fux, C.A., Günthard, H.F., Hachfeld, A., Haerry, D., Hasse, B., Hirsch, H.H., Hoffmann, M., Hösli, I., Huber, M., Kahlert, C.R., Kaiser, L., Keiser, O., Klimkait, T., Kouyos, R.D., Kovari, H., Kusejko, K., Martinetti, G., de Tejada, B.M., Marzolini, C., Metzner, K.J., Müller, N., Nemeth, J., Nicca, D., Paioni, P., Pantaleo, G., Perreau, M., Rauch, A., Schmid, P., Speck, R., Stöckle, M., Tarr, P., Trkola, A., Wandeler, G., and Yerly, S.

Subjects
610 Medicine & health, risk
Abstract

People living with human immunodeficiency virus (PLWH) have significantly increased risk for cardiovascular disease in part due to inflammation and immune dysregulation. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related acquisition and expansion of hematopoietic stem cells due to leukemogenic driver mutations, increases risk for both hematologic malignancy and coronary artery disease (CAD). Since increased inflammation is hypothesized to be both a cause and consequence of CHIP, we hypothesized that PLWH have a greater prevalence of CHIP. We searched for CHIP in multi-ethnic cases from the Swiss HIV Cohort Study (SHCS, n���=���600) and controls from the Atherosclerosis Risk in the Communities study (ARIC, n���=���8111) from blood DNA-derived exome sequences. We observed that HIV is associated with a twofold increase in CHIP prevalence, both in the whole study population and in a subset of 230 cases and 1002 matched controls selected by propensity matching to control for demographic imbalances (SHCS 7%, ARIC 3%, p���=���0.005). We also observed that ASXL1 is the most commonly mutated CHIP-associated gene in PLWH. Our results suggest that CHIP may contribute to the excess cardiovascular risk observed in PLWH.

Published
2022

37. Additive effects of HLA alleles and innate immune genes determine viral outcome in HCV infection

Author

Fitzmaurice, Karen, Hurst, Jacob, Dring, Megan, Rauch, Andri, McLaren, Paul J, Günthard, Huldrych F, Gardiner, Clair, Klenerman, Paul, Courtney, Garry, Crosbie, Orla, Crowe, John, Fanning, Liam, Hegarty, John, Kelleher, Dermot, Lawlor, Emer, Lee, John, McKiernan, Susan, Murray, Frank, Norris, Suzanne, OʼFarrelly, Cliona, Thornton, Leila, Aubert, V, Battegay, M, Bernasconi, E, Böni, J, Bucher, HC, Burton-Jeangros, C, Calmy, A, Cavassini, M, Egger, M, Elzi, L, Fehr, J, Fellay, J, Furrer, H, Fux, CA, Gorgievski, M, Günthard, H, Haerry, D, Hasse, B, Hirsch, HH, Hösli, I, Kahlert, C, Kaiser, L, Keiser, O, Klimkait, T, Kouyos, R, Kovari, H, Ledergerber, B, Martinetti, G, Martinez de Tejada, B, Metzner, K, Müller, N, Nadal, D, Pantaleo, G, Rauch, A, Regenass, S, Rickenbach, M, Rudin, C, Schöni-Affolter, F, Schmid, P, Schultze, D, Schüpbach, J, Speck, R, Tarr, P, Telenti, A, Trkola, A, Vernazza, P, Weber, R, and Yerly, S

Published
2015
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38. Author Correction: The influence of human genetic variation on Epstein-Barr virus sequence diversity

Author

Rüeger, Sina, Hammer, Christian, Loetscher, Alexis, McLaren, Paul J, Lawless, Dylan, Naret, Olivier, Khanna, Nina, Bernasconi, Enos, Cavassini, Matthias, Günthard, Huldrych F, Kahlert, Christian R, Rauch, Andri, Depledge, Daniel P, Morfopoulou, Sofia, Breuer, Judith, Zdobnov, Evgeny, Fellay, Jacques, Swiss HIV Cohort Study, University of Zurich, and Fellay, Jacques

Subjects
10234 Clinic for Infectious Diseases, 1000 Multidisciplinary, 610 Medicine & health
Published
2021

39. The influence of human genetic variation on Epstein-Barr virus sequence diversity

Author

Rüeger, Sina, Hammer, Christian, Loetscher, Alexis, McLaren, Paul J, Lawless, Dylan, Naret, Olivier, Khanna, Nina, Bernasconi, Enos, Cavassini, Matthias, Günthard, Huldrych F, Kahlert, Christian R, Rauch, Andri, Depledge, Daniel P, Morfopoulou, Sofia, Breuer, Judith, Zdobnov, Evgeny, Fellay, Jacques, Swiss HIV Cohort Study, University of Zurich, and Fellay, Jacques

Subjects
10234 Clinic for Infectious Diseases, 1000 Multidisciplinary, 610 Medicine & health
Published
2021

40. Expansion of tissue-resident CD8+ T cells and CD4+ Th17 cells in the nasal mucosa following mRNA COVID-19 vaccination

Author

Ssemaganda, Aloysious, primary, Nguyen, Huong Mai, additional, Nuhu, Faisal, additional, Jahan, Naima, additional, Card, Catherine M., additional, Kiazyk, Sandra, additional, Severini, Giulia, additional, Keynan, Yoav, additional, Su, Ruey-Chyi, additional, Ji, Hezhao, additional, Abrenica, Bernard, additional, McLaren, Paul J., additional, Ball, T. Blake, additional, Bullard, Jared, additional, Van Caeseele, Paul, additional, Stein, Derek, additional, and McKinnon, Lyle R., additional

Published
2021
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41. Genetic variation near CXCL12 is associated with susceptibility to HIV-related non-Hodgkin lymphoma

Author

Thorball, Christian W, Oudot-Mellakh, Tiphaine, Ehsan, Nava, Hammer, Christian, Santoni, Federico A, Niay, Jonathan, Costagliola, Dominique, Goujard, Cécile, Meyer, Laurence, Wang, Sophia S, Hussain, Shehnaz K, Theodorou, Ioannis, Cavassini, Matthias, Rauch, Andri, Battegay, Manuel, Hoffmann, Matthias, Schmid, Patrick, Bernasconi, Enos, Günthard, Huldrych F, Mohammadi, Pejman, McLaren, Paul J, Rabkin, Charles S, Besson, Caroline, Fellay, Jacques, Thorball, Christian W, Oudot-Mellakh, Tiphaine, Ehsan, Nava, Hammer, Christian, Santoni, Federico A, Niay, Jonathan, Costagliola, Dominique, Goujard, Cécile, Meyer, Laurence, Wang, Sophia S, Hussain, Shehnaz K, Theodorou, Ioannis, Cavassini, Matthias, Rauch, Andri, Battegay, Manuel, Hoffmann, Matthias, Schmid, Patrick, Bernasconi, Enos, Günthard, Huldrych F, Mohammadi, Pejman, McLaren, Paul J, Rabkin, Charles S, Besson, Caroline, and Fellay, Jacques

Abstract

Human immunodeficiency virus (HIV) infection is associated with an increased risk of non-Hodgkin lymphoma (NHL). Even in the era of suppressive antiretroviral treatment, HIV-infected individuals remain at higher risk of developing NHL compared to the general population. To identify potential genetic risk loci, we performed case-control genome-wide association studies and a meta-analysis across three cohorts of HIV+ patients of European ancestry, including a total of 278 cases and 1924 matched controls. We observed a significant association with NHL susceptibility in the C-X-C motif chemokine ligand 12 (CXCL12) region on chromosome 10. A fine mapping analysis identified rs7919208 as the most likely causal variant (P = 4.77e-11), with the G>A polymorphism creating a new transcription factor binding site for BATF and JUND. These results suggest a modulatory role of CXCL12 regulation in the increased susceptibility to NHL observed in the HIV-infected population.

Published
2021

42. Expansion of cytotoxic tissue-resident CD8+ T cells and CCR6+CD161+ CD4+ T cells in the nasal mucosa following mRNA COVID-19 vaccination.

Author

Ssemaganda, Aloysious, Nguyen, Huong Mai, Nuhu, Faisal, Jahan, Naima, Card, Catherine M., Kiazyk, Sandra, Severini, Giulia, Keynan, Yoav, Su, Ruey-Chyi, Ji, Hezhao, Abrenica, Bernard, McLaren, Paul J., Ball, T. Blake, Bullard, Jared, Van Caeseele, Paul, Stein, Derek, and McKinnon, Lyle R.

Subjects
NASAL mucosa, COVID-19 vaccines, CYTOTOXIC T cells, T cells, MESSENGER RNA, BLOOD cells, BLOOD flow, VIRUS diseases
Abstract

Vaccines against SARS-CoV-2 have shown high efficacy in clinical trials, yet a full immunologic characterization of these vaccines, particularly within the human upper respiratory tract, is less well known. Here, we enumerate and phenotype T cells in nasal mucosa and blood using flow cytometry before and after vaccination with the Pfizer-BioNTech COVID-19 vaccine (n = 21). Tissue-resident memory (Trm) CD8+ T cells expressing CD69+CD103+ increase in number ~12 days following the first and second doses, by 0.31 and 0.43 log10 cells per swab respectively (p = 0.058 and p = 0.009 in adjusted linear mixed models). CD69+CD103+CD8+ T cells in the blood decrease post-vaccination. Similar increases in nasal CD8+CD69+CD103− T cells are observed, particularly following the second dose. CD4+ cells co-expressing CCR6 and CD161 are also increased in abundance following both doses. Stimulation of nasal CD8+ T cells with SARS-CoV-2 spike peptides elevates expression of CD107a at 2- and 6-months (p = 0.0096) post second vaccine dose, with a subset of donors also expressing increased cytokines. These data suggest that nasal T cells may be induced and contribute to the protective immunity afforded by this vaccine. Whether mRNA SARS-CoV-2 vaccines promote T cells within the nasal mucosa of vaccine recipients is not known. Here the authors show that after mRNA SARS-CoV-2 vaccination, antigen specific T cells can be measured in the nasal mucosa and that these T cells may be localised to respond to a subsequent virus infection. Clinical trial registration NCT04713163 [ABSTRACT FROM AUTHOR]

Published
2022
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45. The role of regulatory T cells in chronic and acute viral infections

Author

Keynan, Yoav, Card, Catherine M., McLaren, Paul J., Dawood, Magdy R., Kasper, Ken, and Fowker, Keith R.

Subjects
T cells -- Physiological aspects, Respiratory tract infections -- Development and progression, Virus diseases -- Development and progression, Health, Health care industry
Published
2008

46. Rectal microbiota diversity in Kenyan MSM is inversely associated with frequency of receptive anal sex, independent of HIV status

Author

Gebrebrhan, Henok, primary, Kambaran, Cheli, additional, Sivro, Aida, additional, Adhiambo, Wendy, additional, Siele, Naomi, additional, Becker, Michael G., additional, Li, Jie, additional, Choi, Sandra, additional, Mwatelah, Ruth S., additional, Reyes, N. Vincent, additional, Akolo, Maureen, additional, Njogu, Peter, additional, Cholette, François, additional, Ho, John, additional, Kim, John, additional, Peterson, Shelley W., additional, Martin, Irene, additional, Sandstrom, Paul, additional, Mehta, Supriya D., additional, Lorway, Robert R., additional, Ball, T. Blake, additional, Kimani, Joshua, additional, Mclaren, Paul J., additional, Ji, Hezhao, additional, and McKinnon, Lyle R., additional

Published
2021
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47. Dissemination of Mycobacterium tuberculosis is associated to a SIGLEC1 null variant that limits antigen exchange via trafficking extracellular vesicles

Author

Benet, Susana, primary, Gálvez, Cristina, additional, Drobniewski, Francis, additional, Kontsevaya, Irina, additional, Arias, Lilibeth, additional, Monguió‐Tortajada, Marta, additional, Erkizia, Itziar, additional, Urrea, Victor, additional, Ong, Ruo‐Yan, additional, Luquin, Marina, additional, Dupont, Maeva, additional, Chojnacki, Jakub, additional, Dalmau, Judith, additional, Cardona, Paula, additional, Neyrolles, Olivier, additional, Lugo‐Villarino, Geanncarlo, additional, Vérollet, Christel, additional, Julián, Esther, additional, Furrer, Hansjakob, additional, Günthard, Huldrych F., additional, Crocker, Paul R., additional, Tapia, Gustavo, additional, Borràs, Francesc E., additional, Fellay, Jacques, additional, McLaren, Paul J., additional, Telenti, Amalio, additional, Cardona, Pere‐Joan, additional, Clotet, Bonaventura, additional, Vilaplana, Cristina, additional, Martinez‐Picado, Javier, additional, and Izquierdo‐Useros, Nuria, additional

Published
2021
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48. Contributors

Author

Ball, T. Blake, primary, Barré-Sinoussi, Françoise, additional, Biasin, Mara, additional, Blankson, Joel N., additional, Broliden, Kristina, additional, Buckheit, Robert W., additional, Card, Catherine M., additional, Clerici, Mario, additional, de Silva, Thushan, additional, Fellay, Jacques, additional, Fowke, Keith R., additional, Jacquelin, Béatrice, additional, Kaul, Rupert, additional, Kaur, Amitinder, additional, Kirchhoff, Frank, additional, Lambotte, Olivier, additional, Landay, Alan L., additional, Luo, Ma, additional, McLaren, Paul J., additional, Moysi, Eirini, additional, Müller-Trutwin, Michaela C., additional, Münch, Jan, additional, Pancino, Gianfranco, additional, Pandrea, Ivona, additional, Pereyra, Florencia, additional, Plummer, Francis A., additional, Rowland-Jones, Sarah, additional, Sáez-Cirión, Asier, additional, Schmitz, Jörn E., additional, Shearer, Gene M., additional, Silvestri, Guido, additional, Telenti, Amalio, additional, Walker, Bruce D, additional, and Zahn, Roland C., additional

Published
2012
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50. A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

Author

Lane, Jérôme, McLaren, Paul J., Dorrell, Lucy, Shianna, Kevin V., Stemke, Amanda, Pelak, Kimberly, Moore, Stephen, Oldenburg, Johannes, Alvarez-Roman, Maria Teresa, Angelillo-Scherrer, Anne, Boehlen, Francoise, Bolton-Maggs, Paula H.B., Brand, Brigit, Brown, Deborah, Chiang, Elaine, Cid-Haro, Ana Rosa, Clotet, Bonaventura, Collins, Peter, Colombo, Sara, Dalmau, Judith, Fogarty, Patrick, Giangrande, Paul, Gringeri, Alessandro, Iyer, Rathi, Katsarou, Olga, Kempton, Christine, Kuriakose, Philip, Lin, Judith, Makris, Mike, Manco-Johnson, Marilyn, Tsakiris, Dimitrios A., Martinez-Picado, Javier, Mauser-Bunschoten, Evelien, Neff, Anne, Oka, Shinichi, Oyesiku, Lara, Parra, Rafael, Peter-Salonen, Kristiina, Powell, Jerry, Recht, Michael, Shapiro, Amy, Stine, Kimo, Talks, Katherine, Telenti, Amalio, Wilde, Jonathan, Yee, Thynn Thynn, Wolinsky, Steven M., Martinson, Jeremy, Hussain, Shehnaz K., Bream, Jay H., Jacobson, Lisa P., Carrington, Mary, Goedert, James J., Haynes, Barton F., McMichael, Andrew J., Goldstein, David B., and Fellay, Jacques

Published
2013
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