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Estimating the contribution of CD4 T cell subset proliferation and differentiation to HIV persistence

Persistence of HIV in people living with HIV (PWH) on suppressive antiretroviral therapy (ART) has been linked to physiological mechanisms of CD4+ T cells. Here, in the same 37 male PWH on ART we measure longitudinal kinetics of HIV DNA and cell turnover rates in five CD4 cell subsets: naïve (T(N)),...

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Autores principales: Reeves, Daniel B., Bacchus-Souffan, Charline, Fitch, Mark, Abdel-Mohsen, Mohamed, Hoh, Rebecca, Ahn, Haelee, Stone, Mars, Hecht, Frederick, Martin, Jeffrey, Deeks, Steven G., Hellerstein, Marc K., McCune, Joseph M., Schiffer, Joshua T., Hunt, Peter W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10545742/
https://www.ncbi.nlm.nih.gov/pubmed/37783718
http://dx.doi.org/10.1038/s41467-023-41521-1
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author Reeves, Daniel B.
Bacchus-Souffan, Charline
Fitch, Mark
Abdel-Mohsen, Mohamed
Hoh, Rebecca
Ahn, Haelee
Stone, Mars
Hecht, Frederick
Martin, Jeffrey
Deeks, Steven G.
Hellerstein, Marc K.
McCune, Joseph M.
Schiffer, Joshua T.
Hunt, Peter W.
author_facet Reeves, Daniel B.
Bacchus-Souffan, Charline
Fitch, Mark
Abdel-Mohsen, Mohamed
Hoh, Rebecca
Ahn, Haelee
Stone, Mars
Hecht, Frederick
Martin, Jeffrey
Deeks, Steven G.
Hellerstein, Marc K.
McCune, Joseph M.
Schiffer, Joshua T.
Hunt, Peter W.
author_sort Reeves, Daniel B.
collection PubMed
description Persistence of HIV in people living with HIV (PWH) on suppressive antiretroviral therapy (ART) has been linked to physiological mechanisms of CD4+ T cells. Here, in the same 37 male PWH on ART we measure longitudinal kinetics of HIV DNA and cell turnover rates in five CD4 cell subsets: naïve (T(N)), stem-cell- (T(SCM)), central- (T(CM)), transitional- (T(TM)), and effector-memory (T(EM)). HIV decreases in T(TM) and T(EM) but not in less-differentiated subsets. Cell turnover is ~10 times faster than HIV clearance in memory subsets, implying that cellular proliferation consistently creates HIV DNA. The optimal mathematical model for these integrated data sets posits HIV DNA also passages between CD4 cell subsets via cellular differentiation. Estimates are heterogeneous, but in an average participant’s year ~10 (in T(N) and T(SCM)) and ~10(4) (in T(CM), T(TM), T(EM)) proviruses are generated by proliferation while ~10(3) proviruses passage via cell differentiation (per million CD4). In simulations, therapies blocking proliferation and/or enhancing differentiation could reduce HIV DNA by 1-2 logs over 3 years. In summary, HIV exploits cellular proliferation and differentiation to persist during ART but clears faster in more proliferative/differentiated CD4 cell subsets and the same physiological mechanisms sustaining HIV might be temporarily modified to reduce it.
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spelling pubmed-105457422023-10-04 Estimating the contribution of CD4 T cell subset proliferation and differentiation to HIV persistence Reeves, Daniel B. Bacchus-Souffan, Charline Fitch, Mark Abdel-Mohsen, Mohamed Hoh, Rebecca Ahn, Haelee Stone, Mars Hecht, Frederick Martin, Jeffrey Deeks, Steven G. Hellerstein, Marc K. McCune, Joseph M. Schiffer, Joshua T. Hunt, Peter W. Nat Commun Article Persistence of HIV in people living with HIV (PWH) on suppressive antiretroviral therapy (ART) has been linked to physiological mechanisms of CD4+ T cells. Here, in the same 37 male PWH on ART we measure longitudinal kinetics of HIV DNA and cell turnover rates in five CD4 cell subsets: naïve (T(N)), stem-cell- (T(SCM)), central- (T(CM)), transitional- (T(TM)), and effector-memory (T(EM)). HIV decreases in T(TM) and T(EM) but not in less-differentiated subsets. Cell turnover is ~10 times faster than HIV clearance in memory subsets, implying that cellular proliferation consistently creates HIV DNA. The optimal mathematical model for these integrated data sets posits HIV DNA also passages between CD4 cell subsets via cellular differentiation. Estimates are heterogeneous, but in an average participant’s year ~10 (in T(N) and T(SCM)) and ~10(4) (in T(CM), T(TM), T(EM)) proviruses are generated by proliferation while ~10(3) proviruses passage via cell differentiation (per million CD4). In simulations, therapies blocking proliferation and/or enhancing differentiation could reduce HIV DNA by 1-2 logs over 3 years. In summary, HIV exploits cellular proliferation and differentiation to persist during ART but clears faster in more proliferative/differentiated CD4 cell subsets and the same physiological mechanisms sustaining HIV might be temporarily modified to reduce it. Nature Publishing Group UK 2023-10-02 /pmc/articles/PMC10545742/ /pubmed/37783718 http://dx.doi.org/10.1038/s41467-023-41521-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Reeves, Daniel B.
Bacchus-Souffan, Charline
Fitch, Mark
Abdel-Mohsen, Mohamed
Hoh, Rebecca
Ahn, Haelee
Stone, Mars
Hecht, Frederick
Martin, Jeffrey
Deeks, Steven G.
Hellerstein, Marc K.
McCune, Joseph M.
Schiffer, Joshua T.
Hunt, Peter W.
Estimating the contribution of CD4 T cell subset proliferation and differentiation to HIV persistence
title Estimating the contribution of CD4 T cell subset proliferation and differentiation to HIV persistence
title_full Estimating the contribution of CD4 T cell subset proliferation and differentiation to HIV persistence
title_fullStr Estimating the contribution of CD4 T cell subset proliferation and differentiation to HIV persistence
title_full_unstemmed Estimating the contribution of CD4 T cell subset proliferation and differentiation to HIV persistence
title_short Estimating the contribution of CD4 T cell subset proliferation and differentiation to HIV persistence
title_sort estimating the contribution of cd4 t cell subset proliferation and differentiation to hiv persistence
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10545742/
https://www.ncbi.nlm.nih.gov/pubmed/37783718
http://dx.doi.org/10.1038/s41467-023-41521-1
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