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Proviral Turnover During Untreated HIV Infection Is Dynamic and Variable Between Hosts, Impacting Reservoir Composition on ART
Human immunodeficiency virus (HIV) can persist as an integrated provirus, in a transcriptionally repressed state, within infected cells. This small yet enduring pool of cellular reservoirs that harbor replication-competent HIV is the main barrier to cure. Entry of viral sequences into cellular reser...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417368/ https://www.ncbi.nlm.nih.gov/pubmed/34489909 http://dx.doi.org/10.3389/fmicb.2021.719153 |
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author | Brooks, Kelsie Omondi, F. Harrison Liang, Richard H. Sudderuddin, Hanwei Jones, Bradley R. Joy, Jeffrey B. Brumme, Chanson J. Hunter, Eric Brumme, Zabrina L. |
author_facet | Brooks, Kelsie Omondi, F. Harrison Liang, Richard H. Sudderuddin, Hanwei Jones, Bradley R. Joy, Jeffrey B. Brumme, Chanson J. Hunter, Eric Brumme, Zabrina L. |
author_sort | Brooks, Kelsie |
collection | PubMed |
description | Human immunodeficiency virus (HIV) can persist as an integrated provirus, in a transcriptionally repressed state, within infected cells. This small yet enduring pool of cellular reservoirs that harbor replication-competent HIV is the main barrier to cure. Entry of viral sequences into cellular reservoirs begins shortly after infection, and cells containing integrated proviral DNA are extremely stable once suppressive antiretroviral therapy (ART) is initiated. During untreated HIV infection however, reservoir turnover is likely to be more dynamic. Understanding these dynamics is important because the longevity of the persisting proviral pool during untreated infection dictates reservoir composition at ART initiation. If the persisting proviral pool turns over slowly pre-ART, then HIV sequences seeded into it during early infection would have a high likelihood of persisting for long periods. However, if pre-ART turnover was rapid, the persisting proviral pool would rapidly shift toward recently circulating HIV sequences. One-way to estimate this turnover rate is from the age distributions of proviruses sampled shortly after therapy initiation: this is because, at the time of sampling, the majority of proviral turnover would have already occurred prior to ART. Recently, methods to estimate a provirus’ age from its sequence have made this possible. Using data from 12 individuals with HIV subtype C for whom proviral ages had been determined phylogenetically, we estimated that the average proviral half-life during untreated infection was 0.78 (range 0.45–2.38) years, which is >15 times faster than that of proviral DNA during suppressive ART. We further show that proviral turnover during untreated infection correlates with both viral setpoint and rate of CD4+ T-cell decline during this period. Overall, our results support dynamic proviral turnover pre-ART in most individuals, which helps explain why many individuals’ reservoirs are skewed toward younger HIV sequences. Broadly, our findings are consistent with the notion that active viral replication creates an environment less favorable to proviral persistence, while viral suppression creates conditions more favorable to persistence, where ART stabilizes the proviral pool by dramatically slowing its rate of decay. Strategies to inhibit this stabilizing effect and/or to enhance reservoir turnover during ART could represent additional strategies to reduce the HIV reservoir. |
format | Online Article Text |
id | pubmed-8417368 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-84173682021-09-05 Proviral Turnover During Untreated HIV Infection Is Dynamic and Variable Between Hosts, Impacting Reservoir Composition on ART Brooks, Kelsie Omondi, F. Harrison Liang, Richard H. Sudderuddin, Hanwei Jones, Bradley R. Joy, Jeffrey B. Brumme, Chanson J. Hunter, Eric Brumme, Zabrina L. Front Microbiol Microbiology Human immunodeficiency virus (HIV) can persist as an integrated provirus, in a transcriptionally repressed state, within infected cells. This small yet enduring pool of cellular reservoirs that harbor replication-competent HIV is the main barrier to cure. Entry of viral sequences into cellular reservoirs begins shortly after infection, and cells containing integrated proviral DNA are extremely stable once suppressive antiretroviral therapy (ART) is initiated. During untreated HIV infection however, reservoir turnover is likely to be more dynamic. Understanding these dynamics is important because the longevity of the persisting proviral pool during untreated infection dictates reservoir composition at ART initiation. If the persisting proviral pool turns over slowly pre-ART, then HIV sequences seeded into it during early infection would have a high likelihood of persisting for long periods. However, if pre-ART turnover was rapid, the persisting proviral pool would rapidly shift toward recently circulating HIV sequences. One-way to estimate this turnover rate is from the age distributions of proviruses sampled shortly after therapy initiation: this is because, at the time of sampling, the majority of proviral turnover would have already occurred prior to ART. Recently, methods to estimate a provirus’ age from its sequence have made this possible. Using data from 12 individuals with HIV subtype C for whom proviral ages had been determined phylogenetically, we estimated that the average proviral half-life during untreated infection was 0.78 (range 0.45–2.38) years, which is >15 times faster than that of proviral DNA during suppressive ART. We further show that proviral turnover during untreated infection correlates with both viral setpoint and rate of CD4+ T-cell decline during this period. Overall, our results support dynamic proviral turnover pre-ART in most individuals, which helps explain why many individuals’ reservoirs are skewed toward younger HIV sequences. Broadly, our findings are consistent with the notion that active viral replication creates an environment less favorable to proviral persistence, while viral suppression creates conditions more favorable to persistence, where ART stabilizes the proviral pool by dramatically slowing its rate of decay. Strategies to inhibit this stabilizing effect and/or to enhance reservoir turnover during ART could represent additional strategies to reduce the HIV reservoir. Frontiers Media S.A. 2021-08-19 /pmc/articles/PMC8417368/ /pubmed/34489909 http://dx.doi.org/10.3389/fmicb.2021.719153 Text en Copyright © 2021 Brooks, Omondi, Liang, Sudderuddin, Jones, Joy, Brumme, Hunter and Brumme. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Microbiology Brooks, Kelsie Omondi, F. Harrison Liang, Richard H. Sudderuddin, Hanwei Jones, Bradley R. Joy, Jeffrey B. Brumme, Chanson J. Hunter, Eric Brumme, Zabrina L. Proviral Turnover During Untreated HIV Infection Is Dynamic and Variable Between Hosts, Impacting Reservoir Composition on ART |
title | Proviral Turnover During Untreated HIV Infection Is Dynamic and Variable Between Hosts, Impacting Reservoir Composition on ART |
title_full | Proviral Turnover During Untreated HIV Infection Is Dynamic and Variable Between Hosts, Impacting Reservoir Composition on ART |
title_fullStr | Proviral Turnover During Untreated HIV Infection Is Dynamic and Variable Between Hosts, Impacting Reservoir Composition on ART |
title_full_unstemmed | Proviral Turnover During Untreated HIV Infection Is Dynamic and Variable Between Hosts, Impacting Reservoir Composition on ART |
title_short | Proviral Turnover During Untreated HIV Infection Is Dynamic and Variable Between Hosts, Impacting Reservoir Composition on ART |
title_sort | proviral turnover during untreated hiv infection is dynamic and variable between hosts, impacting reservoir composition on art |
topic | Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417368/ https://www.ncbi.nlm.nih.gov/pubmed/34489909 http://dx.doi.org/10.3389/fmicb.2021.719153 |
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