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

Neuner-Jehle, Nadia; Zeeb, Marius; Thorball, Christian W; Fellay, Jacques; Metzner, Karin J; Frischknecht, Paul; Neumann, Kathrin; Leeman, Christine; Rauch, Andri; Stöckle, Marcel; Huber, Michael; Perreau, Matthieu; Bernasconi, Enos; Notter, Julia; Hoffmann, Matthias; Leuzinger, Karoline; Günthard, Huldrych F; Pasin, Chloé; Kouyos, Roger D (2024). Using viral diversity to identify HIV-1 variants under HLA-dependent selection in a systematic viral genome-wide screen. (In Press). PLoS pathogens, 20(8), e1012385. Public Library of Science 10.1371/journal.ppat.1012385

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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.

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