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Biphasic decay of intact SHIV genomes following initiation of antiretroviral therapy complicates analysis of interventions targeting the reservoir
The latent reservoir for HIV-1 in resting CD4(+) T cells persists despite antiretroviral therapy (ART) and precludes cure. Reservoir-targeting interventions are evaluated in ART-treated macaques infected with simian immunodeficiency virus (SIV) or simian-human immunodeficiency virus (SHIV). Efficacy...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614214/ https://www.ncbi.nlm.nih.gov/pubmed/37844236 http://dx.doi.org/10.1073/pnas.2313209120 |
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author | Kumar, Mithra R. Fray, Emily J. Bender, Alexandra M. Zitzmann, Carolin Ribeiro, Ruy M. Perelson, Alan S. Barouch, Dan H. Siliciano, Janet D. Siliciano, Robert F. |
author_facet | Kumar, Mithra R. Fray, Emily J. Bender, Alexandra M. Zitzmann, Carolin Ribeiro, Ruy M. Perelson, Alan S. Barouch, Dan H. Siliciano, Janet D. Siliciano, Robert F. |
author_sort | Kumar, Mithra R. |
collection | PubMed |
description | The latent reservoir for HIV-1 in resting CD4(+) T cells persists despite antiretroviral therapy (ART) and precludes cure. Reservoir-targeting interventions are evaluated in ART-treated macaques infected with simian immunodeficiency virus (SIV) or simian-human immunodeficiency virus (SHIV). Efficacy is determined by reservoir measurements before and after the intervention. However, most proviruses persisting in the setting of ART are defective. In addition, intact HIV-1 and SIV genomes undergo complex, multiphasic decay observable when new infection events are blocked by ART. Intervention-induced elimination of latently infected cells must be distinguished from natural decay. Here, we address these issues for SHIV. We describe an intact proviral DNA assay that allows digital counting of SHIV genomes lacking common fatal defects. We show that intact SHIV genomes in circulating CD4(+) T cells undergo biphasic decay during the first year of ART, with a rapid first phase (t(1/2) = 30.1 d) and a slower second phase (t(1/2) = 8.1 mo) that is still more rapid that the slow decay observed in people with HIV-1 on long-term ART (t(1/2) = 3.7 y). In SHIV models, most interventions are tested during 2nd phase decay. Natural 2nd phase decay must be considered in evaluating interventions as most infected cells present at this time do not become part of the stable reservoir. In addition, for interventions tested during 2nd phase decay, a caveat is that the intervention may not be equally effective in people with HIV on long-term ART whose reservoirs are dominated by latently infected cells with a slower decay rate. |
format | Online Article Text |
id | pubmed-10614214 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-106142142023-10-31 Biphasic decay of intact SHIV genomes following initiation of antiretroviral therapy complicates analysis of interventions targeting the reservoir Kumar, Mithra R. Fray, Emily J. Bender, Alexandra M. Zitzmann, Carolin Ribeiro, Ruy M. Perelson, Alan S. Barouch, Dan H. Siliciano, Janet D. Siliciano, Robert F. Proc Natl Acad Sci U S A Biological Sciences The latent reservoir for HIV-1 in resting CD4(+) T cells persists despite antiretroviral therapy (ART) and precludes cure. Reservoir-targeting interventions are evaluated in ART-treated macaques infected with simian immunodeficiency virus (SIV) or simian-human immunodeficiency virus (SHIV). Efficacy is determined by reservoir measurements before and after the intervention. However, most proviruses persisting in the setting of ART are defective. In addition, intact HIV-1 and SIV genomes undergo complex, multiphasic decay observable when new infection events are blocked by ART. Intervention-induced elimination of latently infected cells must be distinguished from natural decay. Here, we address these issues for SHIV. We describe an intact proviral DNA assay that allows digital counting of SHIV genomes lacking common fatal defects. We show that intact SHIV genomes in circulating CD4(+) T cells undergo biphasic decay during the first year of ART, with a rapid first phase (t(1/2) = 30.1 d) and a slower second phase (t(1/2) = 8.1 mo) that is still more rapid that the slow decay observed in people with HIV-1 on long-term ART (t(1/2) = 3.7 y). In SHIV models, most interventions are tested during 2nd phase decay. Natural 2nd phase decay must be considered in evaluating interventions as most infected cells present at this time do not become part of the stable reservoir. In addition, for interventions tested during 2nd phase decay, a caveat is that the intervention may not be equally effective in people with HIV on long-term ART whose reservoirs are dominated by latently infected cells with a slower decay rate. National Academy of Sciences 2023-10-16 2023-10-24 /pmc/articles/PMC10614214/ /pubmed/37844236 http://dx.doi.org/10.1073/pnas.2313209120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Biological Sciences Kumar, Mithra R. Fray, Emily J. Bender, Alexandra M. Zitzmann, Carolin Ribeiro, Ruy M. Perelson, Alan S. Barouch, Dan H. Siliciano, Janet D. Siliciano, Robert F. Biphasic decay of intact SHIV genomes following initiation of antiretroviral therapy complicates analysis of interventions targeting the reservoir |
title | Biphasic decay of intact SHIV genomes following initiation of antiretroviral therapy complicates analysis of interventions targeting the reservoir |
title_full | Biphasic decay of intact SHIV genomes following initiation of antiretroviral therapy complicates analysis of interventions targeting the reservoir |
title_fullStr | Biphasic decay of intact SHIV genomes following initiation of antiretroviral therapy complicates analysis of interventions targeting the reservoir |
title_full_unstemmed | Biphasic decay of intact SHIV genomes following initiation of antiretroviral therapy complicates analysis of interventions targeting the reservoir |
title_short | Biphasic decay of intact SHIV genomes following initiation of antiretroviral therapy complicates analysis of interventions targeting the reservoir |
title_sort | biphasic decay of intact shiv genomes following initiation of antiretroviral therapy complicates analysis of interventions targeting the reservoir |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614214/ https://www.ncbi.nlm.nih.gov/pubmed/37844236 http://dx.doi.org/10.1073/pnas.2313209120 |
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