HIV-1 variants are archived throughout infection and persist in the reservoir

• Type of Material: Article
• Authors: Kelsie Brooks, Emory University; Bradley R. Jones, British Columbia Centre for Excellence in HIV/AIDS; Dario Dilernia, Emory University; Daniel J. Wilkins, Emory University; Daniel T. Claiborne, Emory University; Samantha McInally, Emory University; Jill Gilmour, International AIDS Vaccine Initiative; William Kilembe, Zambia-Emory HIV Research Project, Lusaka, Zambia; Jeffrey B. Joy, British Columbia Centre for Excellence in HIV/AIDS; Susan Allen, Emory University; Zabrina L. Brumme, British Columbia Centre for Excellence in HIV/AIDS; Eric Hunter, Emory University
• Language: English
• Date: 2020-06-01
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2020 Brooks et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1008378
• Title of Journal or Parent Work: PLoS Pathogens
• Volume: 16
• Issue: 6
• Start Page: e1008378
• End Page: e1008378
• Grant/Funding Information: This work was also funded in part by the International AIDS Vaccine Initiative (IAVI) and made possible by the support of many donors, including the United States Agency for International Development (USAID). The full list of IAVI donors is available at http://www.iavi.org.; K.B. was supported with an Action Cycling Atlanta (AV200) Fellowship, and E.H. is a Georgia Research Alliance Eminent Scholar.; Additional funding was provided by the Center for AIDS Research at Emory University (NIH P30 AI050409), and a project grant from the Canadian Institutes for Health Research (PJT-159625 to J.B.J./Z.L.B).; Z.L.B. is supported by a Michael Smith Foundation for Health Research (MSFHR) Scholar Award.; The research reported in this publication was funded in part by: NIH R01 AI064060 (E.H.), NIH R01 AI051231 (E.H.), NIH R21 AI127029 (J.B.J/ Z.L.B.), NIH UM1 AI126617 (Z.L.B.), NIH F31 AI122926 (K.B.), and the Yerkes National Primate Research Center base grant through the Office of Research Infrastructure Programs/OD P51OD11132.
• Keywords: Virology; Microbiology; Phylogenetic analysis; Parasitology; Evolution; Antiretroviral therapy; Decay; Proviruses; Science & Technology; Repication; Identification; Life Sciences & Biomedicine; CD4(+) T-Cells; Immunodeficiency virus type 1; Latent reservoir
• Research Categories: Health Sciences, Public Health; Biology, Microbiology; Biology, Virology; Biology, Parasitology

Abstract

The HIV-1 reservoir consists of latently infected cells that persist despite antiretroviral therapy (ART). Elucidating the proviral genetic composition of the reservoir, particularly in the context of pre-therapy viral diversity, is therefore important to understanding reservoir formation and the persistence of latently infected cells. Here we investigate reservoir proviral variants from 13 Zambian acutely-infected individuals with additional pre-therapy sampling for a unique comparison to the ART-naïve quasispecies. We identified complete transmitted/founder (TF) viruses from seroconversion plasma samples, and additionally amplified and sequenced HIV-1 from plasma obtained one year post-infection and just prior to ART initiation. While the majority of proviral variants in the reservoir were most closely related to viral variants from the latest pre-therapy time point, we also identified reservoir proviral variants dating to or near the time of infection, and to intermediate time points between infection and treatment initiation. Reservoir proviral variants differing by five or fewer nucleotide changes from the TF virus persisted during treatment in five individuals, including proviral variants that exactly matched the TF in two individuals, one of whom had remained ART-naïve for more than six years. Proviral variants during treatment were significantly less divergent from the TF virus than plasma variants present at the last ART-naïve time point. These findings indicate that reservoir proviral variants are archived throughout infection, recapitulating much of the viral diversity that arises throughout untreated HIV-1 infection, and strategies to target and reduce the reservoir must therefore permit for the clearance of proviruses encompassing this extensive diversity.