Relationship between CD4 T cell turnover, cellular differentiation and HIV persistence during ART.
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 w...
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doaj-1c92de8d5c364b769ed3f828c4efac4a2021-07-07T04:30:31ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742021-01-01171e100921410.1371/journal.ppat.1009214Relationship between CD4 T cell turnover, cellular differentiation and HIV persistence during ART.Charline Bacchus-SouffanMark FitchJori SymonsMohamed Abdel-MohsenDaniel B ReevesRebecca HohMars StoneJoseph HiattPeggy KimAbha ChopraHaelee AhnVanessa A YorkDaniel L CameronFrederick M HechtJeffrey N MartinSteven A YuklSimon MallalPaul U CameronSteven G DeeksJoshua T SchifferSharon R LewinMarc K HellersteinJoseph M McCunePeter W HuntThe 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.https://doi.org/10.1371/journal.ppat.1009214 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Charline Bacchus-Souffan Mark Fitch Jori Symons Mohamed Abdel-Mohsen Daniel B Reeves Rebecca Hoh Mars Stone Joseph Hiatt Peggy Kim Abha Chopra Haelee Ahn Vanessa A York Daniel L Cameron Frederick M Hecht Jeffrey N Martin Steven A Yukl Simon Mallal Paul U Cameron Steven G Deeks Joshua T Schiffer Sharon R Lewin Marc K Hellerstein Joseph M McCune Peter W Hunt |
spellingShingle |
Charline Bacchus-Souffan Mark Fitch Jori Symons Mohamed Abdel-Mohsen Daniel B Reeves Rebecca Hoh Mars Stone Joseph Hiatt Peggy Kim Abha Chopra Haelee Ahn Vanessa A York Daniel L Cameron Frederick M Hecht Jeffrey N Martin Steven A Yukl Simon Mallal Paul U Cameron Steven G Deeks Joshua T Schiffer Sharon R Lewin Marc K Hellerstein Joseph M McCune Peter W Hunt Relationship between CD4 T cell turnover, cellular differentiation and HIV persistence during ART. PLoS Pathogens |
author_facet |
Charline Bacchus-Souffan Mark Fitch Jori Symons Mohamed Abdel-Mohsen Daniel B Reeves Rebecca Hoh Mars Stone Joseph Hiatt Peggy Kim Abha Chopra Haelee Ahn Vanessa A York Daniel L Cameron Frederick M Hecht Jeffrey N Martin Steven A Yukl Simon Mallal Paul U Cameron Steven G Deeks Joshua T Schiffer Sharon R Lewin Marc K Hellerstein Joseph M McCune Peter W Hunt |
author_sort |
Charline Bacchus-Souffan |
title |
Relationship between CD4 T cell turnover, cellular differentiation and HIV persistence during ART. |
title_short |
Relationship between CD4 T cell turnover, cellular differentiation and HIV persistence during ART. |
title_full |
Relationship between CD4 T cell turnover, cellular differentiation and HIV persistence during ART. |
title_fullStr |
Relationship between CD4 T cell turnover, cellular differentiation and HIV persistence during ART. |
title_full_unstemmed |
Relationship between CD4 T cell turnover, cellular differentiation and HIV persistence during ART. |
title_sort |
relationship between cd4 t cell turnover, cellular differentiation and hiv persistence during art. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Pathogens |
issn |
1553-7366 1553-7374 |
publishDate |
2021-01-01 |
description |
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. |
url |
https://doi.org/10.1371/journal.ppat.1009214 |
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