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The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo

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      Abstract

      Pharmacologically-induced activation of replication competent proviruses from latency in the presence of antiretroviral treatment (ART) has been proposed as a step towards curing HIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans have yielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremic HIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for 3 weeks while maintaining ART. Lymphocyte histone H3 acetylation, a cellular measure of the pharmacodynamic response to romidepsin, increased rapidly (maximum fold range: 3.7–7.7 relative to baseline) within the first hours following each romidepsin administration. Concurrently, HIV-1 transcription quantified as copies of cell-associated un-spliced HIV-1 RNA increased significantly from baseline during treatment (range of fold-increase: 2.4–5.0; p = 0.03). Plasma HIV-1 RNA increased from <20 copies/mL at baseline to readily quantifiable levels at multiple post-infusion time-points in 5 of 6 patients (range 46–103 copies/mL following the second infusion, p = 0.04). Importantly, romidepsin did not decrease the number of HIV-specific T cells or inhibit T cell cytokine production. Adverse events (all grade 1–2) were consistent with the known side effects of romidepsin. In conclusion, romidepsin safely induced HIV-1 transcription resulting in plasma HIV-1 RNA that was readily detected with standard commercial assays demonstrating that significant reversal of HIV-1 latency in vivo is possible without blunting T cell-mediated immune responses. These finding have major implications for future trials aiming to eradicate the HIV-1 reservoir.Trial Registrationclinicaltrials.gov NTC02092116

      Author Summary

      One proposed way of curing HIV is to activate virus transcription and kill latently infected cells while the presence of antiretroviral therapy prevents spreading the infection. Induction of global T cell activation by mitogenic or other potent activators effectively reverses HIV-1 from latency ex vivo, but such compounds are generally too toxic for clinical use. Therefore, investigating the capacity of small molecule latency reversing agents to induce production of virus without causing global T cell activation has been a top research priority for scientists in recent years. In the present clinical trial, we demonstrate that significant viral reactivation can be safely induced using the depsipeptide romidepsin (HDAC inhibitor) in long-term suppressed HIV-1 individuals on antiretroviral therapy. Following each romidepsin infusion, we observed clear increases in lymphocyte H3 acetylation, HIV-1 transcription, and plasma HIV-1 RNA. Importantly, this reversal of HIV-1 latency could be measured using standard clinical assays for detection of plasma HIV-1 RNA. Furthermore, romidepsin did not alter the proportion of HIV-specific T cells or inhibit T cell cytokine production which is critically important for future trials combining HDAC inhibitors with interventions (e.g. therapeutic HIV-1 vaccination) designed to enhance killing of latently infected cells.

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      Most cited references 47

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      Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy.

      The hypothesis that quiescent CD4+ T lymphocytes carrying proviral DNA provide a reservoir for human immunodeficiency virus-type 1 (HIV-1) in patients on highly active antiretroviral therapy (HAART) was examined. In a study of 22 patients successfully treated with HAART for up to 30 months, replication-competent virus was routinely recovered from resting CD4+ T lymphocytes. The frequency of resting CD4+ T cells harboring latent HIV-1 was low, 0.2 to 16.4 per 10(6) cells, and, in cross-sectional analysis, did not decrease with increasing time on therapy. The recovered viruses generally did not show mutations associated with resistance to the relevant antiretroviral drugs. This reservoir of nonevolving latent virus in resting CD4+ T cells should be considered in deciding whether to terminate treatment in patients who respond to HAART.
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        ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays.

        ELDA is a software application for limiting dilution analysis (LDA), with particular attention to the needs of stem cell assays. It is the first limiting dilution analysis software to provide meaningful confidence intervals for all LDA data sets, including those with 0% or 100% responses. Other features include a test of the adequacy of the single-hit hypothesis, tests for frequency differences between multiple data sets, and the ability to take advantage of cases where the number of cells in the sample is counted exactly. A webtool at http://bioinf.wehi.edu.au/software/elda/ provides an easy user interface.
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          HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation.

          HIV persists in a reservoir of latently infected CD4(+) T cells in individuals treated with highly active antiretroviral therapy (HAART). Here we identify central memory (T(CM)) and transitional memory (T(TM)) CD4(+) T cells as the major cellular reservoirs for HIV and find that viral persistence is ensured by two different mechanisms. HIV primarily persists in T(CM) cells in subjects showing reconstitution of the CD4(+) compartment upon HAART. This reservoir is maintained through T cell survival and low-level antigen-driven proliferation and is slowly depleted with time. In contrast, proviral DNA is preferentially detected in T(TM) cells from aviremic individuals with low CD4(+) counts and higher amounts of interleukin-7-mediated homeostatic proliferation, a mechanism that ensures the persistence of these cells. Our results suggest that viral eradication might be achieved through the combined use of strategic interventions targeting viral replication and, as in cancer, drugs that interfere with the self renewal and persistence of proliferating memory T cells.
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            Author and article information

            Affiliations
            [1 ]Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
            [2 ]Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
            [3 ]Aarhus Institute for Advanced Studies, Aarhus University, Denmark
            [4 ]Kirby Institute, University of New South Wales Medicine, University of New South Wales Australia, Sydney, Australia
            [5 ]Division of Immunology and Allergy, Lausanne University Hospital, Lausanne, Switzerland
            [6 ]Bionor Pharma ASA, Oslo, Norway
            [7 ]Centre de Recherche du CHUM, Montreal, Quebec, Canada
            [8 ]Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Faculty of Medicine, Montreal, Quebec, Canada
            John Hopkins University, UNITED STATES
            Author notes

            I have read the journal's policy and the authors of this manuscript have the following competing interests: MS is an employee of Bionor Pharma ASA and has shares in the company. KK is a consultant to Bionor Pharma ASA. The other authors declare no competing interests. This does not alter our adherence to all PLOS policies on sharing data and materials.

            Conceived and designed the experiments: OSS TAR LØ MT SL. Performed the experiments: OSS SL MEG CRB RO ASK MHS PWD SKN WJHC KKK GP MS KK RF NC TAR MT. Analyzed the data: OSS SL CRB RO ASK MHS PWD SKN WJHC KKK GP RF NC TAR MT. Contributed reagents/materials/analysis tools: CRB RO ASK MHS PWD SKN WJHC KKK GP MS KK RF NC. Wrote the paper: OSS TAR LØ MT RO PWD.

            Contributors
            Role: Editor
            Journal
            PLoS Pathog
            PLoS Pathog
            plos
            plospath
            PLoS Pathogens
            Public Library of Science (San Francisco, CA USA )
            1553-7366
            1553-7374
            17 September 2015
            September 2015
            : 11
            : 9
            26379282
            4575032
            10.1371/journal.ppat.1005142
            PPATHOGENS-D-15-01124
            (Editor)

            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

            Counts
            Figures: 5, Tables: 2, Pages: 22
            Product
            Funding
            This study was funded by a grant from the Research Council of Norway (GLOBVAC) program (Nr: 235955) and Bionor Pharma ASA. The Research Council of Norway had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Bionor Pharma ASA contributed to the study design and the preparation of the manuscript.
            Categories
            Research Article
            Custom metadata
            Data underlying the findings described in the manuscript are available in the manuscript itself. Biological specimens may be obtained through a material transfer agreement. Requests should be directed to OSS.

            Infectious disease & Microbiology

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