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      Dynamics of HIV Latency and Reactivation in a Primary CD4+ T Cell Model

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          Abstract

          HIV latency is a major obstacle to curing infection. Current strategies to eradicate HIV aim at increasing transcription of the latent provirus. In the present study we observed that latently infected CD4+ T cells from HIV-infected individuals failed to produce viral particles upon ex vivo exposure to SAHA (vorinostat), despite effective inhibition of histone deacetylases. To identify steps that were not susceptible to the action of SAHA or other latency reverting agents, we used a primary CD4+ T cell model, joint host and viral RNA sequencing, and a viral-encoded reporter. This model served to investigate the characteristics of latently infected cells, the dynamics of HIV latency, and the process of reactivation induced by various stimuli. During latency, we observed persistence of viral transcripts but only limited viral translation. Similarly, the reactivating agents SAHA and disulfiram successfully increased viral transcription, but failed to effectively enhance viral translation, mirroring the ex vivo data. This study highlights the importance of post-transcriptional blocks as one mechanism leading to HIV latency that needs to be relieved in order to purge the viral reservoir.

          Author Summary

          HIV-infected individuals must receive lifelong antiviral therapy because treatment discontinuation generally results in rapid viral rebound. The field has identified a state of latency at the level of transcription of the integrated provirus as the major mechanism of persistence. A number of drugs are now tested that aim at inducing viral transcription as a step to purge the reservoir. The assessment of viral production in cells from HIV-infected individuals with optimal viral suppression revealed the failure of SAHA/vorinostat to efficiently generate viral particle production. To further investigate and characterize the process of latency at the transcriptome level, and the response to SAHA as well as various reactivating agents, we use a model of primary CD4+ lymphocytes. The main observation from this study is that viral transcripts persist during latency, and that the accumulation of viral transcripts does not result in efficient viral protein expression upon reactivation with agents such as SAHA. Our data suggest that post-transcriptional blocks also contribute to latency, and that additional strategies need to be explored to efficiently purge the viral reservoir.

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          Most cited references39

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          Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation.

          Highly active antiretroviral therapy (HAART) suppresses HIV-1 replication but cannot eliminate the virus because HIV-1 establishes latent infection. Interruption of HAART leads to a rapid rebound of viremia, so life-long treatment is required. Efforts to purge the latent reservoir have focused on reactivating latent proviruses without inducing global T cell activation. However, the killing of the infected cells after virus reactivation, which is essential for elimination of the reservoir, has not been assessed. Here we show that after reversal of latency in an in vitro model, infected resting CD4(+) T cells survived despite viral cytopathic effects, even in the presence of autologous cytolytic T lymphocytes (CTLs) from most patients on HAART. Antigen-specific stimulation of patient CTLs led to efficient killing of infected cells. These results demonstrate that stimulating HIV-1-specific CTLs prior to reactivating latent HIV-1 may be essential for successful eradication efforts and should be considered in future clinical trials. Copyright © 2012 Elsevier Inc. All rights reserved.
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            HIV: Shock and kill.

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              Revisiting global gene expression analysis.

              Gene expression analysis is a widely used and powerful method for investigating the transcriptional behavior of biological systems, for classifying cell states in disease, and for many other purposes. Recent studies indicate that common assumptions currently embedded in experimental and analytical practices can lead to misinterpretation of global gene expression data. We discuss these assumptions and describe solutions that should minimize erroneous interpretation of gene expression data from multiple analysis platforms. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                May 2014
                29 May 2014
                : 10
                : 5
                : e1004156
                Affiliations
                [1 ]Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland
                [2 ]Swiss Institute of Bioinformatics, Basel and Lausanne, Switzerland
                [3 ]Institute of Microbiology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
                [4 ]School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
                [5 ]Service of Infectious Diseases, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
                [6 ]University of Lausanne, Lausanne, Switzerland
                Fred Hutchinson Cancer Research Center, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: AT AC NB JF. Performed the experiments: MM CT AC RM. Analyzed the data: PM JdI. Wrote the paper: AT AC PM JdI NB JF. Clinical work: MC. Designed the web-based interactive analysis tool: IB.

                Article
                PPATHOGENS-D-14-00181
                10.1371/journal.ppat.1004156
                4038609
                24875931
                309bb81f-7e21-48ba-af42-3c189910cdf9
                Copyright @ 2014

                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 credited.

                History
                : 21 January 2014
                : 18 April 2014
                Page count
                Pages: 14
                Funding
                This work was supported by the Swiss National Science Foundation (31003A_146579), the FP7-HEALTH 2012-INNOVATION-1 (305762) and by a Grand Challenges Explorations award from the Bill and Melinda Gates Foundation. JdI is recipient of a fellowship of the Swiss National Science Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Viral Pathogens
                Immunodeficiency Viruses
                HIV
                Virology
                Viral Persistence and Latency
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogenesis
                Host-Pathogen Interactions

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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