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Cells producing residual viremia during antiretroviral treatment appear to contribute to rebound viremia following interruption of treatment
During antiretroviral therapy (ART) that suppresses HIV replication to below the limit-of-quantification, virions produced during ART can be detected at low frequencies in the plasma, termed residual viremia (RV). We hypothesized that a reservoir of HIV-infected cells actively produce and release vi...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473585/ https://www.ncbi.nlm.nih.gov/pubmed/32841299 http://dx.doi.org/10.1371/journal.ppat.1008791 |
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author | Aamer, Hadega A. McClure, Jan Ko, Daisy Maenza, Janine Collier, Ann C. Coombs, Robert W. Mullins, James I. Frenkel, Lisa M. |
author_facet | Aamer, Hadega A. McClure, Jan Ko, Daisy Maenza, Janine Collier, Ann C. Coombs, Robert W. Mullins, James I. Frenkel, Lisa M. |
author_sort | Aamer, Hadega A. |
collection | PubMed |
description | During antiretroviral therapy (ART) that suppresses HIV replication to below the limit-of-quantification, virions produced during ART can be detected at low frequencies in the plasma, termed residual viremia (RV). We hypothesized that a reservoir of HIV-infected cells actively produce and release virions during ART that are potentially infectious, and that following ART-interruption, these virions can complete full-cycles of replication and contribute to rebound viremia. Therefore, we studied the dynamics of RV sequence variants in 3 participants who initiated ART after ~3 years of infection and were ART-suppressed for >6 years prior to self-initiated ART-interruptions. Longitudinal RV C2V5env sequences were compared to sequences from pre-ART plasma, supernatants of quantitative viral outgrowth assays (QVOA) of cells collected during ART, post-ART-interruption plasma, and ART-re-suppression plasma. Identical, “putatively clonal,” RV sequences comprised 8–84% of sequences from each timepoint. The majority of RV sequences were genetically similar to those from plasma collected just prior to ART-initiation, but as the duration of ART-suppression increased, an increasing proportion of RV variants were similar to sequences from earlier in infection. Identical sequences were detected in RV over a median of 3 years (range: 0.3–8.2) of ART-suppression. RV sequences were identical to pre-ART plasma viruses (5%), infectious viruses induced in QVOA (4%) and rebound viruses (5%) (total n = 21/154 (14%) across the 3 participants). RV sequences identical to ART-interruption “rebound” sequences were detected 0.1–7.4 years prior to ART-interruption. RV variant prevalence and persistence were not associated with detection of the variant among rebound sequences. Shortly after ART-re-suppression, variants that had been replicating during ART-interruptions were detected as RV (n = 5). These studies show a dynamic, virion-producing HIV reservoir that contributes to rekindling infection upon ART-interruption. The persistence of identical RV variants over years suggests that a subpopulation of HIV-infected clones frequently or continuously produce virions that may resist immune clearance; this suggests that cure strategies should target this active as well as latent reservoirs. |
format | Online Article Text |
id | pubmed-7473585 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-74735852020-09-14 Cells producing residual viremia during antiretroviral treatment appear to contribute to rebound viremia following interruption of treatment Aamer, Hadega A. McClure, Jan Ko, Daisy Maenza, Janine Collier, Ann C. Coombs, Robert W. Mullins, James I. Frenkel, Lisa M. PLoS Pathog Research Article During antiretroviral therapy (ART) that suppresses HIV replication to below the limit-of-quantification, virions produced during ART can be detected at low frequencies in the plasma, termed residual viremia (RV). We hypothesized that a reservoir of HIV-infected cells actively produce and release virions during ART that are potentially infectious, and that following ART-interruption, these virions can complete full-cycles of replication and contribute to rebound viremia. Therefore, we studied the dynamics of RV sequence variants in 3 participants who initiated ART after ~3 years of infection and were ART-suppressed for >6 years prior to self-initiated ART-interruptions. Longitudinal RV C2V5env sequences were compared to sequences from pre-ART plasma, supernatants of quantitative viral outgrowth assays (QVOA) of cells collected during ART, post-ART-interruption plasma, and ART-re-suppression plasma. Identical, “putatively clonal,” RV sequences comprised 8–84% of sequences from each timepoint. The majority of RV sequences were genetically similar to those from plasma collected just prior to ART-initiation, but as the duration of ART-suppression increased, an increasing proportion of RV variants were similar to sequences from earlier in infection. Identical sequences were detected in RV over a median of 3 years (range: 0.3–8.2) of ART-suppression. RV sequences were identical to pre-ART plasma viruses (5%), infectious viruses induced in QVOA (4%) and rebound viruses (5%) (total n = 21/154 (14%) across the 3 participants). RV sequences identical to ART-interruption “rebound” sequences were detected 0.1–7.4 years prior to ART-interruption. RV variant prevalence and persistence were not associated with detection of the variant among rebound sequences. Shortly after ART-re-suppression, variants that had been replicating during ART-interruptions were detected as RV (n = 5). These studies show a dynamic, virion-producing HIV reservoir that contributes to rekindling infection upon ART-interruption. The persistence of identical RV variants over years suggests that a subpopulation of HIV-infected clones frequently or continuously produce virions that may resist immune clearance; this suggests that cure strategies should target this active as well as latent reservoirs. Public Library of Science 2020-08-25 /pmc/articles/PMC7473585/ /pubmed/32841299 http://dx.doi.org/10.1371/journal.ppat.1008791 Text en © 2020 Aamer et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Aamer, Hadega A. McClure, Jan Ko, Daisy Maenza, Janine Collier, Ann C. Coombs, Robert W. Mullins, James I. Frenkel, Lisa M. Cells producing residual viremia during antiretroviral treatment appear to contribute to rebound viremia following interruption of treatment |
title | Cells producing residual viremia during antiretroviral treatment appear to contribute to rebound viremia following interruption of treatment |
title_full | Cells producing residual viremia during antiretroviral treatment appear to contribute to rebound viremia following interruption of treatment |
title_fullStr | Cells producing residual viremia during antiretroviral treatment appear to contribute to rebound viremia following interruption of treatment |
title_full_unstemmed | Cells producing residual viremia during antiretroviral treatment appear to contribute to rebound viremia following interruption of treatment |
title_short | Cells producing residual viremia during antiretroviral treatment appear to contribute to rebound viremia following interruption of treatment |
title_sort | cells producing residual viremia during antiretroviral treatment appear to contribute to rebound viremia following interruption of treatment |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473585/ https://www.ncbi.nlm.nih.gov/pubmed/32841299 http://dx.doi.org/10.1371/journal.ppat.1008791 |
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