@article{83d2269150b94462b9e2939238e0f62a,
title = "Antiretroviral therapy reveals triphasic decay of intact SIV genomes and persistence of ancestral variants",
abstract = "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.",
keywords = "SIV, clonal expansion, decay, defective provirus, latent reservoir",
author = "Fray, {Emily J.} and Fengting Wu and Simonetti, {Francesco R.} and Carolin Zitzmann and Narmada Sambaturu and Carmen Molina-Paris and Bender, {Alexandra M.} and Liu, {Po Ting} and Ventura, {John D.} and Wiseman, {Roger W.} and O'Connor, {David H.} and Romas Geleziunas and Thomas Leitner and Ribeiro, {Ruy M.} and Perelson, {Alan S.} and Barouch, {Dan H.} and Siliciano, {Janet D.} and Siliciano, {Robert F.}",
note = "Funding Information: This work was supported by the NIH Martin Delaney Collaboratory grant UM1AI164556 to D.H.B. and by Howard Hughes Medical Institute to R.F.S. Animal studies were supported by AI124377 , AI128751 , AI149670 , AI164556 , and AI169615 for D.H.B. F.R.S is supported by the Office of the NIH Director and National Institute of Dental and Craniofacial Research ( DP5OD031834 ). Portions of this work were performed under the auspices of the US Department of Energy through Los Alamos National Laboratory, which is operated by Triad National Security, LLC , for the National Nuclear Security Administration of the US Department of Energy (contract 89233218CNA000001 ). Support was also provided by NIH grants R01-AI028433 , R01-OD011095 , P01-AI131365 (to A.S.P.), R01-AI15270301 , and UM1-AI164561 (to R.M.R.). Funding Information: This work was supported by the NIH Martin Delaney Collaboratory grant UM1AI164556 to D.H.B. and by Howard Hughes Medical Institute to R.F.S. Animal studies were supported by AI124377, AI128751, AI149670, AI164556, and AI169615 for D.H.B. F.R.S is supported by the Office of the NIH Director and National Institute of Dental and Craniofacial Research (DP5OD031834). Portions of this work were performed under the auspices of the US Department of Energy through Los Alamos National Laboratory, which is operated by Triad National Security, LLC, for the National Nuclear Security Administration of the US Department of Energy (contract 89233218CNA000001). Support was also provided by NIH grants R01-AI028433, R01-OD011095, P01-AI131365 (to A.S.P.), R01-AI15270301, and UM1-AI164561 (to R.M.R.). E.J.F. R.F.S. J.D.S. and D.H.B. designed the study. E.J.F. R.F.S. J.D.S. D.H.B. J.D.V. and F.W. F.R.S. C.Z. N.S. C.M.P. T.L. R.M.R. and A.S.P. participated in discussion and interpretation of the results. E.J.F. and F.W. performed the experiments. A.M.B. provided samples that were used for assay development and optimization. D.H.B. P.L. J.D.V. and R.G. provided samples, information, and drugs related to the animal work. C.Z. N.S. C.M.P, T.L. R.M.R. A.S.P. performed the mathematical modeling. R.W. and D.H.O. performed MHC genotyping and analysis. E.J.F. wrote the manuscript. R.F.S. and J.D.S. revised the manuscript. revised the manuscript. E.J.F. F.R.S. C.Z. N.S. T.L. R.M.R. A.S.P. and R.F.S. performed the data analysis, Aspects of HIV-1 IPDA are subject of a patent application PCT/ US16/28822 filed by Johns Hopkins University. R.F.S. is an inventor on this application. Accelevir Diagnostics holds an exclusive license for this patent application. R.F.S. holds no equity interest in Accelevir Diagnostics. Publisher Copyright: {\textcopyright} 2023 The Authors",
year = "2023",
month = mar,
day = "8",
doi = "10.1016/j.chom.2023.01.016",
language = "English (US)",
volume = "31",
pages = "356--372.e5",
journal = "Cell Host and Microbe",
issn = "1931-3128",
publisher = "Cell Press",
number = "3",
}