The latent reservoir of inducible, infectious HIV-1 does not decrease despite decades of antiretroviral therapy
HIV-1 persists in a latent reservoir in resting CD4+ T cells despite antiretroviral therapy (ART). The reservoir decays slowly over the first 7 years of ART (t1/2 = 44 months). However, whether decay continues with long-term ART is unclear. Recent integration site studies indicate gradual selection...
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2023-09-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI171554 |
| _version_ | 1797634410959339520 |
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| author | Natalie F. McMyn Joseph Varriale Emily J. Fray Carolin Zitzmann Hannah MacLeod Jun Lai Anushka Singhal Milica Moskovljevic Mauro A. Garcia Brianna M. Lopez Vivek Hariharan Kyle Rhodehouse Kenneth Lynn Pablo Tebas Karam Mounzer Luis J. Montaner Erika Benko Colin Kovacs Rebecca Hoh Francesco R. Simonetti Gregory M. Laird Steven G. Deeks Ruy M. Ribeiro Alan S. Perelson Robert F. Siliciano Janet M. Siliciano |
| author_facet | Natalie F. McMyn Joseph Varriale Emily J. Fray Carolin Zitzmann Hannah MacLeod Jun Lai Anushka Singhal Milica Moskovljevic Mauro A. Garcia Brianna M. Lopez Vivek Hariharan Kyle Rhodehouse Kenneth Lynn Pablo Tebas Karam Mounzer Luis J. Montaner Erika Benko Colin Kovacs Rebecca Hoh Francesco R. Simonetti Gregory M. Laird Steven G. Deeks Ruy M. Ribeiro Alan S. Perelson Robert F. Siliciano Janet M. Siliciano |
| author_sort | Natalie F. McMyn |
| collection | DOAJ |
| description | HIV-1 persists in a latent reservoir in resting CD4+ T cells despite antiretroviral therapy (ART). The reservoir decays slowly over the first 7 years of ART (t1/2 = 44 months). However, whether decay continues with long-term ART is unclear. Recent integration site studies indicate gradual selection against inducible, intact proviruses, raising speculation that decades of ART might allow treatment interruption without viral rebound. Therefore, we measured the reservoir in 42 people on long-term ART (mean 22 years) using a quantitative viral outgrowth assay. After 7 years of ART, there was no long-term decrease in the frequency of inducible, replication-competent proviruses but rather an increase with an estimated doubling time of 23 years. Another reservoir assay, the intact proviral DNA assay, confirmed that reservoir decay with t1/2 of 44 months did not continue with long-term ART. The lack of decay reflected proliferation of infected cells. Most inducible, replication-competent viruses (79.8%) had env sequences identical to those of other isolates from the same sample. Thus, although integration site analysis indicates changes in reservoir composition, the proliferation of CD4+ T cells counteracts decay, maintaining the frequency of inducible, replication-competent proviruses at roughly constant levels over the long term. These results reinforce the need for lifelong ART. |
| first_indexed | 2024-03-11T12:07:17Z |
| format | Article |
| id | doaj.art-16cb14484f3b4a688aeb5fd64cf309ef |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:07:17Z |
| publishDate | 2023-09-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-16cb14484f3b4a688aeb5fd64cf309ef2023-11-07T16:20:46ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-09-0113317The latent reservoir of inducible, infectious HIV-1 does not decrease despite decades of antiretroviral therapyNatalie F. McMynJoseph VarrialeEmily J. FrayCarolin ZitzmannHannah MacLeodJun LaiAnushka SinghalMilica MoskovljevicMauro A. GarciaBrianna M. LopezVivek HariharanKyle RhodehouseKenneth LynnPablo TebasKaram MounzerLuis J. MontanerErika BenkoColin KovacsRebecca HohFrancesco R. SimonettiGregory M. LairdSteven G. DeeksRuy M. RibeiroAlan S. PerelsonRobert F. SilicianoJanet M. SilicianoHIV-1 persists in a latent reservoir in resting CD4+ T cells despite antiretroviral therapy (ART). The reservoir decays slowly over the first 7 years of ART (t1/2 = 44 months). However, whether decay continues with long-term ART is unclear. Recent integration site studies indicate gradual selection against inducible, intact proviruses, raising speculation that decades of ART might allow treatment interruption without viral rebound. Therefore, we measured the reservoir in 42 people on long-term ART (mean 22 years) using a quantitative viral outgrowth assay. After 7 years of ART, there was no long-term decrease in the frequency of inducible, replication-competent proviruses but rather an increase with an estimated doubling time of 23 years. Another reservoir assay, the intact proviral DNA assay, confirmed that reservoir decay with t1/2 of 44 months did not continue with long-term ART. The lack of decay reflected proliferation of infected cells. Most inducible, replication-competent viruses (79.8%) had env sequences identical to those of other isolates from the same sample. Thus, although integration site analysis indicates changes in reservoir composition, the proliferation of CD4+ T cells counteracts decay, maintaining the frequency of inducible, replication-competent proviruses at roughly constant levels over the long term. These results reinforce the need for lifelong ART.https://doi.org/10.1172/JCI171554AIDS/HIVVirology |
| spellingShingle | Natalie F. McMyn Joseph Varriale Emily J. Fray Carolin Zitzmann Hannah MacLeod Jun Lai Anushka Singhal Milica Moskovljevic Mauro A. Garcia Brianna M. Lopez Vivek Hariharan Kyle Rhodehouse Kenneth Lynn Pablo Tebas Karam Mounzer Luis J. Montaner Erika Benko Colin Kovacs Rebecca Hoh Francesco R. Simonetti Gregory M. Laird Steven G. Deeks Ruy M. Ribeiro Alan S. Perelson Robert F. Siliciano Janet M. Siliciano The latent reservoir of inducible, infectious HIV-1 does not decrease despite decades of antiretroviral therapy The Journal of Clinical Investigation AIDS/HIV Virology |
| title | The latent reservoir of inducible, infectious HIV-1 does not decrease despite decades of antiretroviral therapy |
| title_full | The latent reservoir of inducible, infectious HIV-1 does not decrease despite decades of antiretroviral therapy |
| title_fullStr | The latent reservoir of inducible, infectious HIV-1 does not decrease despite decades of antiretroviral therapy |
| title_full_unstemmed | The latent reservoir of inducible, infectious HIV-1 does not decrease despite decades of antiretroviral therapy |
| title_short | The latent reservoir of inducible, infectious HIV-1 does not decrease despite decades of antiretroviral therapy |
| title_sort | latent reservoir of inducible infectious hiv 1 does not decrease despite decades of antiretroviral therapy |
| topic | AIDS/HIV Virology |
| url | https://doi.org/10.1172/JCI171554 |
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