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Comparative Analysis of Measures of Viral Reservoirs in HIV-1 Eradication Studies
HIV-1 reservoirs preclude virus eradication in patients receiving highly active antiretroviral therapy (HAART). The best characterized reservoir is a small, difficult-to-quantify pool of resting memory CD4(+) T cells carrying latent but replication-competent viral genomes. Because strategies targeti...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573107/ https://www.ncbi.nlm.nih.gov/pubmed/23459007 http://dx.doi.org/10.1371/journal.ppat.1003174 |
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author | Eriksson, Susanne Graf, Erin H. Dahl, Viktor Strain, Matthew C. Yukl, Steven A. Lysenko, Elena S. Bosch, Ronald J. Lai, Jun Chioma, Stanley Emad, Fatemeh Abdel-Mohsen, Mohamed Hoh, Rebecca Hecht, Frederick Hunt, Peter Somsouk, Ma Wong, Joseph Johnston, Rowena Siliciano, Robert F. Richman, Douglas D. O'Doherty, Una Palmer, Sarah Deeks, Steven G. Siliciano, Janet D. |
author_facet | Eriksson, Susanne Graf, Erin H. Dahl, Viktor Strain, Matthew C. Yukl, Steven A. Lysenko, Elena S. Bosch, Ronald J. Lai, Jun Chioma, Stanley Emad, Fatemeh Abdel-Mohsen, Mohamed Hoh, Rebecca Hecht, Frederick Hunt, Peter Somsouk, Ma Wong, Joseph Johnston, Rowena Siliciano, Robert F. Richman, Douglas D. O'Doherty, Una Palmer, Sarah Deeks, Steven G. Siliciano, Janet D. |
author_sort | Eriksson, Susanne |
collection | PubMed |
description | HIV-1 reservoirs preclude virus eradication in patients receiving highly active antiretroviral therapy (HAART). The best characterized reservoir is a small, difficult-to-quantify pool of resting memory CD4(+) T cells carrying latent but replication-competent viral genomes. Because strategies targeting this latent reservoir are now being tested in clinical trials, well-validated high-throughput assays that quantify this reservoir are urgently needed. Here we compare eleven different approaches for quantitating persistent HIV-1 in 30 patients on HAART, using the original viral outgrowth assay for resting CD4(+) T cells carrying inducible, replication-competent viral genomes as a standard for comparison. PCR-based assays for cells containing HIV-1 DNA gave infected cell frequencies at least 2 logs higher than the viral outgrowth assay, even in subjects who started HAART during acute/early infection. This difference may reflect defective viral genomes. The ratio of infected cell frequencies determined by viral outgrowth and PCR-based assays varied dramatically between patients. Although strong correlations with the viral outgrowth assay could not be formally excluded for most assays, correlations achieved statistical significance only for integrated HIV-1 DNA in peripheral blood mononuclear cells and HIV-1 RNA/DNA ratio in rectal CD4(+) T cells. Residual viremia was below the limit of detection in many subjects and did not correlate with the viral outgrowth assays. The dramatic differences in infected cell frequencies and the lack of a precise correlation between culture and PCR-based assays raise the possibility that the successful clearance of latently infected cells may be masked by a larger and variable pool of cells with defective proviruses. These defective proviruses are detected by PCR but may not be affected by reactivation strategies and may not require eradication to accomplish an effective cure. A molecular understanding of the discrepancy between infected cell frequencies measured by viral outgrowth versus PCR assays is an urgent priority in HIV-1 cure research. |
format | Online Article Text |
id | pubmed-3573107 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-35731072013-03-01 Comparative Analysis of Measures of Viral Reservoirs in HIV-1 Eradication Studies Eriksson, Susanne Graf, Erin H. Dahl, Viktor Strain, Matthew C. Yukl, Steven A. Lysenko, Elena S. Bosch, Ronald J. Lai, Jun Chioma, Stanley Emad, Fatemeh Abdel-Mohsen, Mohamed Hoh, Rebecca Hecht, Frederick Hunt, Peter Somsouk, Ma Wong, Joseph Johnston, Rowena Siliciano, Robert F. Richman, Douglas D. O'Doherty, Una Palmer, Sarah Deeks, Steven G. Siliciano, Janet D. PLoS Pathog Research Article HIV-1 reservoirs preclude virus eradication in patients receiving highly active antiretroviral therapy (HAART). The best characterized reservoir is a small, difficult-to-quantify pool of resting memory CD4(+) T cells carrying latent but replication-competent viral genomes. Because strategies targeting this latent reservoir are now being tested in clinical trials, well-validated high-throughput assays that quantify this reservoir are urgently needed. Here we compare eleven different approaches for quantitating persistent HIV-1 in 30 patients on HAART, using the original viral outgrowth assay for resting CD4(+) T cells carrying inducible, replication-competent viral genomes as a standard for comparison. PCR-based assays for cells containing HIV-1 DNA gave infected cell frequencies at least 2 logs higher than the viral outgrowth assay, even in subjects who started HAART during acute/early infection. This difference may reflect defective viral genomes. The ratio of infected cell frequencies determined by viral outgrowth and PCR-based assays varied dramatically between patients. Although strong correlations with the viral outgrowth assay could not be formally excluded for most assays, correlations achieved statistical significance only for integrated HIV-1 DNA in peripheral blood mononuclear cells and HIV-1 RNA/DNA ratio in rectal CD4(+) T cells. Residual viremia was below the limit of detection in many subjects and did not correlate with the viral outgrowth assays. The dramatic differences in infected cell frequencies and the lack of a precise correlation between culture and PCR-based assays raise the possibility that the successful clearance of latently infected cells may be masked by a larger and variable pool of cells with defective proviruses. These defective proviruses are detected by PCR but may not be affected by reactivation strategies and may not require eradication to accomplish an effective cure. A molecular understanding of the discrepancy between infected cell frequencies measured by viral outgrowth versus PCR assays is an urgent priority in HIV-1 cure research. Public Library of Science 2013-02-14 /pmc/articles/PMC3573107/ /pubmed/23459007 http://dx.doi.org/10.1371/journal.ppat.1003174 Text en © 2013 Eriksson 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 Eriksson, Susanne Graf, Erin H. Dahl, Viktor Strain, Matthew C. Yukl, Steven A. Lysenko, Elena S. Bosch, Ronald J. Lai, Jun Chioma, Stanley Emad, Fatemeh Abdel-Mohsen, Mohamed Hoh, Rebecca Hecht, Frederick Hunt, Peter Somsouk, Ma Wong, Joseph Johnston, Rowena Siliciano, Robert F. Richman, Douglas D. O'Doherty, Una Palmer, Sarah Deeks, Steven G. Siliciano, Janet D. Comparative Analysis of Measures of Viral Reservoirs in HIV-1 Eradication Studies |
title | Comparative Analysis of Measures of Viral Reservoirs in HIV-1 Eradication Studies |
title_full | Comparative Analysis of Measures of Viral Reservoirs in HIV-1 Eradication Studies |
title_fullStr | Comparative Analysis of Measures of Viral Reservoirs in HIV-1 Eradication Studies |
title_full_unstemmed | Comparative Analysis of Measures of Viral Reservoirs in HIV-1 Eradication Studies |
title_short | Comparative Analysis of Measures of Viral Reservoirs in HIV-1 Eradication Studies |
title_sort | comparative analysis of measures of viral reservoirs in hiv-1 eradication studies |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573107/ https://www.ncbi.nlm.nih.gov/pubmed/23459007 http://dx.doi.org/10.1371/journal.ppat.1003174 |
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