Associations of functional HLA class I groups with HIV viral load in a heterogeneous cohort

Human Leucocyte Antigen (HLA) class I alleles are the main host genetic factors involved in controlling HIV-1 viral load (VL). Nevertheless, HLA diversity has proven a significant challenge in association studies. We assessed how accounting for binding affinities of HLA class I alleles to HIV-1 peptides facilitate association testing of HLA with HIV-1 VL in a heterogeneous cohort from the Strategic Timing of AntiRetroviral Treatment (START) study. We imputed HLA class I alleles from host genetic data (2,546 HIV+ participants) and sampled immunopeptidomes from 2,079 host-paired viral genomes (targeted amplicon sequencing). We predicted HLA class I binding affinities to HIV-1 and unspecific peptides, grouping alleles into functional clusters through consensus clustering. These functional HLA class I clusters were used to test associations with HIV VL. We identified four clades totalling 30 HLA alleles accounting for 11.4% variability in VL. We highlight HLA-B*57:01 and B*57:03 as functionally similar but yet overrepresented in distinct ethnic groups, showing when combined a protective association with HIV+ VL (log, β −0.25; adj. p-value < 0.05). We further demonstrate only a slight power reduction when using unspecific immunopeptidomes, facilitating the use of the inferred functional HLA groups in other studies. The outlined computational approach provides a robust and efficient way to incorporate HLA function and peptide diversity, aiding clinical association studies in heterogeneous cohorts. To facilitate access to the proposed methods and results we provide an interactive application for exploring data. ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by the Danish National Research Foundation (DNRF126) and the National Institute of Allergy and Infectious Diseases, Division of Clinical Research and Division of AIDS (National Institutes of Health grants UM1-AI068641, UM1-AI120197 and U01-AI136780). The START trial was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health Clinical Center, National Cancer Institute, National Heart, Lung, and Blood Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (France), National Health and Medical Research Council (Australia), National Research Foundation (Denmark), Bundes Ministerium fur Bildung und Forschung (Germany), European AIDS Treatment Network, Medical Research Council (United Kingdom), National Institute for Health Research, National Health Service (United Kingdom), and the University of Minnesota. Antiretroviral drugs were donated to the central drug repository by AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, and Merck. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) gave approval for accessing the data to conduct this work. Written consent for the study and genetic analyses were obtained from the participants and ethical approval was given by site ethics review committees represented in the INSIGHT network International Coordinating Centers: The University of Minnesota -- Minneapolis, Minnesota, USA. Copenhagen HIV Programme (CHIP) -- Copenhagen, Denmark. Medical Research Council (MRC) Clinical Trials Unit -- London, United Kingdom. National Centre in HIV Epidemiology and Clinical Research (NCHECR), University of New South Wales -- Sydney, Australia. The Institute for Clinical Research at the Veterans Affairs Medical Center -- Washington, D.C., USA. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) [https://persimune-health-informatics.shinyapps.io/PAW2022Zucco_\_HLA\_HIV_INSIGHT/][2] [1]: pending:yes [2]: https://persimune-health-informatics.shinyapps.io/PAW2022Zucco__HLA_HIV_INSIGHT/