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

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

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.