Journal Article

Using viral diversity to identify HIV-1 variants under HLA-dependent selection in a systematic viral genome-wide screen

Notter, Julia, Zeeb, Marius, Günthard, Huldrych F., Neumann, Kathrin, Kouyos, Roger D., Hoffmann, Matthias, Fellay, Jacques, Frischknecht, Paul, Rauch, Andri, Stöckle, Marcel, Pasin, Chloé, Leeman, Christine, Neuner-Jehle, Nadia, Thorball, Christian W., Metzner, Karin J., Perreau, Matthieu, Huber, Michael, Bernasconi, Enos, Leuzinger, Karoline

2024

Overview

The pathogenesis of HIV-1 infection is governed by a highly dynamic, time-dependent interaction between the host and the viral genome. In this study, we developed a novel systematic approach to assess the host-virus interaction, using average pairwise viral diversity as a proxy for time since infection, and applied this method to nearly whole viral genome sequences (n = 4,464), human leukocyte antigen (HLA) genotyping data (n = 1,044), and viral RNA load (VL) measurements during the untreated chronic phase (n = 829) of Swiss HIV Cohort Study participants. Our systematic genome-wide screen revealed for 98 HLA/viral-variant pairs a signature of immune-driven selection in the form of an HLA-dependent effect of infection time on the presence of HIV amino acid variants. Of these pairs, 12 were found to have an effect on VL. Furthermore, 28/58 pairs were validated by time-to-event analyses and 48/92 by computational HLA-epitope predictions. Our diversity-based approach allows a powerful and systematic investigation of the interaction between the virus and cellular immunity, revealing a notable subset of such interaction effects. From an evolutionary perspective, these observations underscore the complexity of HLA-mediated selection pressures on the virus that shape viral evolution and pathogenesis.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: AIDS vaccines / Amino acids / Analysis / Antigens / Biology and Life Sciences / Cell-mediated immunity / Cohort analysis / Cohort Studies / Diagnosis / Dosage and administration / Epitopes / Gene sequencing / Genetic aspects / Genetic screening / Genetic Variation / Genome, Viral / Genomes / Genotyping / Grants / Histocompatibility antigen HLA / Histocompatibility antigens / HIV / HIV infection / HIV Infections - genetics / HIV Infections - immunology / HIV Infections - virology / HIV-1 - genetics / HIV-1 - immunology / HLA Antigens - genetics / HLA Antigens - immunology / HLA histocompatibility antigens / Hospitals / Host-Pathogen Interactions - genetics / Host-Pathogen Interactions - immunology / Human immunodeficiency virus / Humans / Infections / Leukocytes / Longitudinal studies / Medicine and Health Sciences / Mutation / Pathogenesis / Research and Analysis Methods / Risk factors / Selection, Genetic / Survival analysis / T cell receptors / Testing / Time dependence / Viral Load / Viruses