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

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.

Informations de copyright

Copyright: © 2024 Neuner-Jehle et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Déclaration de conflit d'intérêts

I have read the journal’s policy and the authors of this manuscript have the following competing interests: K.J.M. has received travel grants and honoraria from Gilead Sciences, Roche Diagnostics, GlaxoSmithKline, Merck Sharp & Dohme, Bristol-Myers Squibb, ViiV, and Abbott; and the University of Zurich has received research grants from Gilead Science, Novartis, Roche, and Merck Sharp & Dohme for studies in which K.J.M. serves as principal investigator, and advisory board honoraria from Gilead Sciences and ViiV. A.R. reports support to his institution for advisory board and/or travel grants from MSD, Gilead Sciences, Pfizer, and Moderna, and an investigator-initiated trial (IIT) grant from Gilead Sciences. All honoraria went to his home institution, not to A.R. personally, and all honoraria were provided outside of the submitted work. M.S. reports advisory board consultations from Gilead, ViiV, MSD, paid to his institution, and travel grants for conferences from Gilead, paid to his institution. E.B.’s institution has received research grants from Gilead and Merck unrelated to this work; E.B.’s institution has also received consultancy fees and travel grants from Gilead, ViiV, Merck, Pfizer, Astra Zeneca, Moderna, Abbvie, and Ely Lilly. J.N. has received travel grants from Gilead. H.F.G. has received grants from the Yvonne-Jacob Foundation, the Clinical Research Priority Program of the University of Zurich, and Gilead Sciences, and, outside of this study, grants for unrestricted research from the Swiss HIV Cohort Study, the Swiss National Science Foundation, the National Institutes of Health, the Bill and Melinda Gates Foundation, Gilead, and ViiV; and personal fees as a consultant for Merck, ViiV Healthcare, and Gilead Sciences and as a member of the Data and Safety Monitoring Board for Merck. H.F.G.’s institution has received educational grants unrelated to this work from Gilead, ViiV, MSD, Abbvie, Pfizer, and Sandoz. C.P. has received fellowships from the Collegium Helveticum. R.D.K. has received grants from Gilead Sciences, the National Institutes of Health, the Swiss National Science Foundation, and the Swiss HIV Cohort Study. N.N.J. has received support from the Swiss National Science Foundation and the Swiss HIV Cohort Study. All other authors report no potential conflicts of interest.