Antiretroviral therapy reveals triphasic decay of intact SIV genomes and persistence of ancestral variants

Fray, Emily J.; Wu, Fengting; Simonetti, Francesco R.; Zitzmann, Carolin; Sambaturu, Narmada; Molina-Paris, Carmen; Bender, Alexandra M.; Liu, Po-Ting; Ventura, John D.; Wiseman, Roger W.; O’Connor, David H.; Geleziunas, Romas; Leitner, Thomas Kenneth; Ribeiro, Ruy Miguel; Perelson, Alan S.; Barouch, Dan H.; Siliciano, Janet D.; Siliciano, Robert F.

doi:10.1016/j.chom.2023.01.016

Antiretroviral therapy reveals triphasic decay of intact SIV genomes and persistence of ancestral variants

Journal Article · Wed Mar 08 00:00:00 EST 2023 · Cell Host & Microbe

DOI:https://doi.org/10.1016/j.chom.2023.01.016· OSTI ID:1963653

Fray, Emily J. ^[1]; Wu, Fengting ^[1]; Simonetti, Francesco R. ^[1]; Zitzmann, Carolin ^[2]; Sambaturu, Narmada ^[2]; Molina-Paris, Carmen ^[2]; Bender, Alexandra M. ^[1]; Liu, Po-Ting ^[3]; Ventura, John D. ^[3]; Wiseman, Roger W. ^[4]; O’Connor, David H. ^[4]; Geleziunas, Romas ^[5]; ^[2]; ^[2]; ^[2]; Barouch, Dan H. ^[3]; Siliciano, Janet D. ^[1]; Siliciano, Robert F. ^[6]

Johns Hopkins Univ., Baltimore, MD (United States). School of Medicine
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Beth Israel Deaconess Medical Center, Boston, MA (United States)
Wisconsin National Primate Research Center, Madison, WI (United States)
Gilead Sciences, Foster City, CA (United States)
Johns Hopkins Univ., Baltimore, MD (United States). School of Medicine; Howard Hughes Medical Inst., Baltimore, MD (United States)

The decay kinetics of HIV-1-infected cells are critical to understand virus persistence. We evaluated the frequency of simian immunodeficiency virus (SIV)-infected cells for 4 years of antiretroviral therapy (ART). The intact proviral DNA assay (IPDA) and an assay for hypermutated proviruses revealed short- and long-term infected cell dynamics in macaques starting ART ~1 year after infection. Intact SIV genomes in circulating CD4+T cells showed triphasic decay with an initial phase slower than the decay of the plasma virus, a second phase faster than the second phase decay of intact HIV-1, and a stable third phase reached after 1.6–2.9 years. Hypermutated proviruses showed bi- or mono-phasic decay, reflecting different selective pressures. Viruses replicating at ART initiation had mutations conferring antibody escape. With time on ART, viruses with fewer mutations became more prominent, reflecting decay of variants replicating at ART initiation. Collectively, these findings confirm ART efficacy and indicate that cells enter the reservoir throughout untreated infection.

View Accepted Manuscript (DOE)

Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: National Institutes of Health (NIH), National Institute of Dental and Craniofacial Research (NIDCR); USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: 89233218CNA000001

OSTI ID:: 1963653

Report Number(s):: LA-UR-22-30227

Journal Information:: Cell Host & Microbe, Journal Name: Cell Host & Microbe Journal Issue: 3 Vol. 31; ISSN 1931-3128

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Proviruses with identical sequences comprise a large fraction of the replication-competent HIV reservoir Bui, John K.; Sobolewski, Michele D.; Keele, Brandon F. PLOS Pathogens, Vol. 13, Issue 3 https://doi.org/10.1371/journal.ppat.1006283	journal	March 2017
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60 APPLIED LIFE SCIENCES
SIV
non-human primates
latency
biological science
clonal expansion
decay
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latent reservoir

Antiretroviral therapy reveals triphasic decay of intact SIV genomes and persistence of ancestral variants

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