Relationship between CD4 T cell turnover, cellular differentiation and HIV persistence during ART

C. Bacchus-Souffan; M. Fitch; J. Symons; M. Abdel-Mohsen; D.B. Reeves; R. Hoh; M. Stone; J. Hiatt; P. Kim; A. Chopra; H. Ahn; V.A. York; D.L. Cameron; F.M. Hecht; J.N. Martin; S.A. Yukl; S. Mallal; P.U. Cameron; S.G. Deeks; J.T. Schiffer; S.R. Lewin; M.K. Hellerstein; J.M. McCune; P.W. Hunt

doi:10.1371/journal.ppat.1009214

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Relationship between CD4 T cell turnover, cellular differentiation and HIV persistence during ART

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Relationship between CD4 T cell turnover, cellular differentiation and HIV persistence during ART

C. Bacchus-Souffan, M. Fitch, J. Symons, M. Abdel-Mohsen, D.B. Reeves, R. Hoh, M. Stone, J. Hiatt, P. Kim, A. Chopra, …

PLoS Pathogens, Vol.17(1), e1009214

2021

DOI: https://doi.org/10.1371/journal.ppat.1009214

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Abstract

The precise role of CD4 T cell turnover in maintaining HIV persistence during antiretroviral therapy (ART) has not yet been well characterized. In resting CD4 T cell subpopulations from 24 HIV-infected ART-suppressed and 6 HIV-uninfected individuals, we directly measured cellular turnover by heavy water labeling, HIV reservoir size by integrated HIV-DNA (intDNA) and cell-associated HIV-RNA (caRNA), and HIV reservoir clonality by proviral integration site sequencing. Compared to HIV-negatives, ART-suppressed individuals had similar fractional replacement rates in all subpopulations, but lower absolute proliferation rates of all subpopulations other than effector memory (TEM) cells, and lower plasma IL-7 levels (p = 0.0004). Median CD4 T cell half-lives decreased with cell differentiation from naïve to TEM cells (3 years to 3 months, p<0.001). TEM had the fastest replacement rates, were most highly enriched for intDNA and caRNA, and contained the most clonal proviral expansion. Clonal proviruses detected in less mature subpopulations were more expanded in TEM, suggesting that they were maintained through cell differentiation. Earlier ART initiation was associated with lower levels of intDNA, caRNA and fractional replacement rates. In conclusion, circulating integrated HIV proviruses appear to be maintained both by slow turnover of immature CD4 subpopulations, and by clonal expansion as well as cell differentiation into effector cells with faster replacement rates.

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Title: Relationship between CD4 T cell turnover, cellular differentiation and HIV persistence during ART
Authors/Creators: C. Bacchus-Souffan (Author/Creator) - University of California, San Francisco
M. Fitch (Author/Creator) - University of California, Berkeley
J. Symons (Author/Creator) - Peter Doherty Institute
M. Abdel-Mohsen (Author/Creator) - The Wistar Institute
D.B. Reeves (Author/Creator) - Fred Hutch Cancer Center
R. Hoh (Author/Creator) - San Francisco General Hospital
M. Stone (Author/Creator) - University of California, San Francisco
J. Hiatt (Author/Creator) - University of California, San Francisco
P. Kim (Author/Creator) - San Francisco VA Medical Center
A. Chopra (Author/Creator) - Vanderbilt University Medical Center
H. Ahn (Author/Creator) - University of California, San Francisco
V.A. York (Author/Creator) - University of California, San Francisco
D.L. Cameron (Author/Creator) - Walter and Eliza Hall Institute of Medical Research
F.M. Hecht (Author/Creator) - San Francisco General Hospital
J.N. Martin (Author/Creator) - San Francisco General Hospital
S.A. Yukl (Author/Creator) - San Francisco General Hospital
S. Mallal (Author/Creator) - Vanderbilt University Medical Center
P.U. Cameron (Author/Creator) - Peter Doherty Institute
S.G. Deeks (Author/Creator) - San Francisco General Hospital
J.T. Schiffer (Author/Creator) - Fred Hutch Cancer Center
S.R. Lewin (Author/Creator) - Peter Doherty Institute
M.K. Hellerstein (Author/Creator) - University of California, Berkeley
J.M. McCune (Author/Creator) - Gates Foundation
P.W. Hunt (Author/Creator) - University of California, San Francisco
Publication Details: PLoS Pathogens, Vol.17(1), e1009214
Publisher: Public Library of Science
Identifiers: 991005544075407891
Copyright: © 2021 Bacchus-Souffan et al.
Murdoch Affiliation: Institute for Immunology and Infectious Diseases
Language: English
Resource Type: Journal article

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.66 HIV; 1.66.46 HIV Pathogenesis
Web Of Science research areas: Microbiology; Parasitology; Virology
ESI research areas: Microbiology