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CD4(+) T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence during ART
HIV persists in a small pool of latently infected cells despite antiretroviral therapy (ART). Identifying cellular markers expressed at the surface of these cells may lead to novel therapeutic strategies to reduce the size of the HIV reservoir. We hypothesized that CD4(+) T cells expressing immune c...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944956/ https://www.ncbi.nlm.nih.gov/pubmed/27415008 http://dx.doi.org/10.1371/journal.ppat.1005761 |
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author | Fromentin, Rémi Bakeman, Wendy Lawani, Mariam B. Khoury, Gabriela Hartogensis, Wendy DaFonseca, Sandrina Killian, Marisela Epling, Lorrie Hoh, Rebecca Sinclair, Elizabeth Hecht, Frederick M. Bacchetti, Peter Deeks, Steven G. Lewin, Sharon R. Sékaly, Rafick-Pierre Chomont, Nicolas |
author_facet | Fromentin, Rémi Bakeman, Wendy Lawani, Mariam B. Khoury, Gabriela Hartogensis, Wendy DaFonseca, Sandrina Killian, Marisela Epling, Lorrie Hoh, Rebecca Sinclair, Elizabeth Hecht, Frederick M. Bacchetti, Peter Deeks, Steven G. Lewin, Sharon R. Sékaly, Rafick-Pierre Chomont, Nicolas |
author_sort | Fromentin, Rémi |
collection | PubMed |
description | HIV persists in a small pool of latently infected cells despite antiretroviral therapy (ART). Identifying cellular markers expressed at the surface of these cells may lead to novel therapeutic strategies to reduce the size of the HIV reservoir. We hypothesized that CD4(+) T cells expressing immune checkpoint molecules would be enriched in HIV-infected cells in individuals receiving suppressive ART. Expression levels of 7 immune checkpoint molecules (PD-1, CTLA-4, LAG-3, TIGIT, TIM-3, CD160 and 2B4) as well as 4 markers of HIV persistence (integrated and total HIV DNA, 2-LTR circles and cell-associated unspliced HIV RNA) were measured in PBMCs from 48 virally suppressed individuals. Using negative binomial regression models, we identified PD-1, TIGIT and LAG-3 as immune checkpoint molecules positively associated with the frequency of CD4(+) T cells harboring integrated HIV DNA. The frequency of CD4(+) T cells co-expressing PD-1, TIGIT and LAG-3 independently predicted the frequency of cells harboring integrated HIV DNA. Quantification of HIV genomes in highly purified cell subsets from blood further revealed that expressions of PD-1, TIGIT and LAG-3 were associated with HIV-infected cells in distinct memory CD4(+) T cell subsets. CD4(+) T cells co-expressing the three markers were highly enriched for integrated viral genomes (median of 8.2 fold compared to total CD4(+) T cells). Importantly, most cells carrying inducible HIV genomes expressed at least one of these markers (median contribution of cells expressing LAG-3, PD-1 or TIGIT to the inducible reservoir = 76%). Our data provide evidence that CD4(+) T cells expressing PD-1, TIGIT and LAG-3 alone or in combination are enriched for persistent HIV during ART and suggest that immune checkpoint blockers directed against these receptors may represent valuable tools to target latently infected cells in virally suppressed individuals. |
format | Online Article Text |
id | pubmed-4944956 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-49449562016-08-08 CD4(+) T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence during ART Fromentin, Rémi Bakeman, Wendy Lawani, Mariam B. Khoury, Gabriela Hartogensis, Wendy DaFonseca, Sandrina Killian, Marisela Epling, Lorrie Hoh, Rebecca Sinclair, Elizabeth Hecht, Frederick M. Bacchetti, Peter Deeks, Steven G. Lewin, Sharon R. Sékaly, Rafick-Pierre Chomont, Nicolas PLoS Pathog Research Article HIV persists in a small pool of latently infected cells despite antiretroviral therapy (ART). Identifying cellular markers expressed at the surface of these cells may lead to novel therapeutic strategies to reduce the size of the HIV reservoir. We hypothesized that CD4(+) T cells expressing immune checkpoint molecules would be enriched in HIV-infected cells in individuals receiving suppressive ART. Expression levels of 7 immune checkpoint molecules (PD-1, CTLA-4, LAG-3, TIGIT, TIM-3, CD160 and 2B4) as well as 4 markers of HIV persistence (integrated and total HIV DNA, 2-LTR circles and cell-associated unspliced HIV RNA) were measured in PBMCs from 48 virally suppressed individuals. Using negative binomial regression models, we identified PD-1, TIGIT and LAG-3 as immune checkpoint molecules positively associated with the frequency of CD4(+) T cells harboring integrated HIV DNA. The frequency of CD4(+) T cells co-expressing PD-1, TIGIT and LAG-3 independently predicted the frequency of cells harboring integrated HIV DNA. Quantification of HIV genomes in highly purified cell subsets from blood further revealed that expressions of PD-1, TIGIT and LAG-3 were associated with HIV-infected cells in distinct memory CD4(+) T cell subsets. CD4(+) T cells co-expressing the three markers were highly enriched for integrated viral genomes (median of 8.2 fold compared to total CD4(+) T cells). Importantly, most cells carrying inducible HIV genomes expressed at least one of these markers (median contribution of cells expressing LAG-3, PD-1 or TIGIT to the inducible reservoir = 76%). Our data provide evidence that CD4(+) T cells expressing PD-1, TIGIT and LAG-3 alone or in combination are enriched for persistent HIV during ART and suggest that immune checkpoint blockers directed against these receptors may represent valuable tools to target latently infected cells in virally suppressed individuals. Public Library of Science 2016-07-14 /pmc/articles/PMC4944956/ /pubmed/27415008 http://dx.doi.org/10.1371/journal.ppat.1005761 Text en © 2016 Fromentin 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Fromentin, Rémi Bakeman, Wendy Lawani, Mariam B. Khoury, Gabriela Hartogensis, Wendy DaFonseca, Sandrina Killian, Marisela Epling, Lorrie Hoh, Rebecca Sinclair, Elizabeth Hecht, Frederick M. Bacchetti, Peter Deeks, Steven G. Lewin, Sharon R. Sékaly, Rafick-Pierre Chomont, Nicolas CD4(+) T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence during ART |
title | CD4(+) T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence during ART |
title_full | CD4(+) T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence during ART |
title_fullStr | CD4(+) T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence during ART |
title_full_unstemmed | CD4(+) T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence during ART |
title_short | CD4(+) T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence during ART |
title_sort | cd4(+) t cells expressing pd-1, tigit and lag-3 contribute to hiv persistence during art |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944956/ https://www.ncbi.nlm.nih.gov/pubmed/27415008 http://dx.doi.org/10.1371/journal.ppat.1005761 |
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