Migle Gabrielaite1, Marc Bennedbæk2, Adrian G Zucco2, Christina Ekenberg2, Daniel D Murray2, Virginia L Kan3, Giota Touloumi4, Linos Vandekerckhove5, Dan Turner6, James Neaton7, H Clifford Lane8, Sandra Safo7, Alejandro Arenas-Pinto9, Mark N Polizzotto10, Huldrych F Günthard11,12, Jens D Lundgren2, Rasmus L Marvig1. 1. Centre for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark. 2. Centre of Excellence for Health, Immunity, and Infections, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 3. Veterans Affairs Medical Center, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA. 4. Department of Hygiene, Epidemiology, and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Athens, Greece. 5. HIV Cure Research Center, Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent University Hospital, Ghent, Belgium. 6. Crusaid Kobler AIDS Center, Tel-Aviv Sourasky Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 7. Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA. 8. Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. 9. Medical Research Council Clinical Trials Unit, University College London, London, United Kingdom. 10. Kirby Institute for Infection and Immunity, University of New South Wales, Sydney, Australia. 11. Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, Zürich, Switzerland. 12. Institute of Medical Virology, University of Zürich, Zürich, Switzerland.
Abstract
BACKGROUND: Understanding the genetic interplay between human hosts and infectious pathogens is crucial for how we interpret virulence factors. Here, we tested for associations between HIV and host genetics, and interactive genetic effects on viral load (VL) in HIV-positive antiretroviral treatment-naive clinical trial participants. METHODS: HIV genomes were sequenced and the encoded amino acid (AA) variants were associated with VL, human single nucleotide polymorphisms (SNPs), and imputed HLA alleles using generalized linear models with Bonferroni correction. RESULTS: Human (388 501 SNPs) and HIV (3010 variants) genetic data were available for 2122 persons. Four HIV variants were associated with VL (P < 1.66 × 10-5). Twelve HIV variants were associated with a range of 1-512 human SNPs (P < 4.28 × 10-11). We found 46 associations between HLA alleles and HIV variants (P < 1.29 × 10-7). HIV variants and immunotypes when analyzed separately were associated with lower VL, whereas the opposite was true when analyzed in concert. Epitope binding predictions supported our observations. CONCLUSIONS: Our results show the importance of immunotype specificity on viral antigenic determinants, and the identified genetic interplay emphasizes that viral and human genetics should be studied in the context of each other.Clinical Trials Registration: NCT00867048.
BACKGROUND: Understanding the genetic interplay between human hosts and infectious pathogens is crucial for how we interpret virulence factors. Here, we tested for associations between HIV and host genetics, and interactive genetic effects on viral load (VL) in HIV-positive antiretroviral treatment-naive clinical trial participants. METHODS: HIV genomes were sequenced and the encoded amino acid (AA) variants were associated with VL, human single nucleotide polymorphisms (SNPs), and imputed HLA alleles using generalized linear models with Bonferroni correction. RESULTS: Human (388 501 SNPs) and HIV (3010 variants) genetic data were available for 2122 persons. Four HIV variants were associated with VL (P < 1.66 × 10-5). Twelve HIV variants were associated with a range of 1-512 human SNPs (P < 4.28 × 10-11). We found 46 associations between HLA alleles and HIV variants (P < 1.29 × 10-7). HIV variants and immunotypes when analyzed separately were associated with lower VL, whereas the opposite was true when analyzed in concert. Epitope binding predictions supported our observations. CONCLUSIONS: Our results show the importance of immunotype specificity on viral antigenic determinants, and the identified genetic interplay emphasizes that viral and human genetics should be studied in the context of each other.Clinical Trials Registration: NCT00867048.
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