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      Increasing procaspase 8 expression using repurposed drugs to induce HIV infected cell death in ex vivo patient cells

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          Abstract

          HIV persists because a reservoir of latently infected CD4 T cells do not express viral proteins and are indistinguishable from uninfected cells. One approach to HIV cure suggests that reactivating HIV will activate cytotoxic pathways; yet when tested in vivo, reactivating cells do not die sufficiently to reduce cell-associated HIV DNA levels. We recently showed that following reactivation from latency, HIV infected cells generate the HIV specific cytotoxic protein Casp8p41 which is produced by HIV protease cleaving procaspase 8. However, cell death is prevented, possibly due to low procaspase 8 expression. Here, we tested whether increasing procaspase 8 levels in CD4 T cells will produce more Casp8p41 following HIV reactivation, causing more reactivated cells to die. Screening 1277 FDA approved drugs identified 168 that increased procaspase 8 expression by at least 1.7-fold. Of these 30 were tested for anti-HIV effects in an acute HIV IIIb infection model, and 9 drugs at physiologic relevant levels significantly reduced cell-associated HIV DNA. Primary CD4 T cells from ART suppressed HIV patients were treated with one of these 9 drugs and reactivated with αCD3/αCD28. Four drugs significantly increased Casp8p41 levels following HIV reactivation, and decreased total cell associated HIV DNA levels (flurbiprofen: p = 0.014; doxycycline: p = 0.044; indomethacin: p = 0.025; bezafibrate: P = 0.018) without effecting the viability of uninfected cells. Thus procaspase 8 levels can be increased pharmacologically and, in the context of HIV reactivation, increase Casp8p41 causing death of reactivating cells and decreased HIV DNA levels. Future studies will be required to define the clinical utility of this or similar approaches.

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          Most cited references 95

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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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            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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              Recovery of replication-competent HIV despite prolonged suppression of plasma viremia.

              In evaluating current combination drug regimens for treatment of human immunodeficiency virus (HIV) disease, it is important to determine the existence of viral reservoirs. After depletion of CD8 cells from the peripheral blood mononuclear cells (PBMCs) of both patients and normal donors, activation of patient CD4 lymphocytes with immobilized antibodies to CD3 and CD28 enabled the isolation of virus from PBMCs of six patients despite the suppression of their plasma HIV RNA to fewer than 50 copies per milliliter for up to 2 years. Partial sequencing of HIV pol revealed no new drug resistance mutations or discernible evolution, providing evidence for viral latency rather than drug failure.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                19 June 2017
                2017
                : 12
                : 6
                Affiliations
                [1 ]Division of Infectious Disease, Mayo Clinic Rochester, Rochester, MN, United States of America
                [2 ]Office of Translation to Practice, Mayo Clinic Rochester, Rochester, MN, United States of America
                [3 ]Division of Infectious Diseases, University of Minnesota, Minneapolis, MN, United States of America
                [4 ]HIV Program, Hennepin County Medical Center, Minnneapolis, MN, United States of America
                [5 ]Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, Canada
                University Hospital Zurich, SWITZERLAND
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: RS NWC GDB ADB.

                • Data curation: RS NWC.

                • Formal analysis: RS NWC SN GDB TC ADB.

                • Funding acquisition: NWC ADB.

                • Investigation: RS NWC GDB SN AP.

                • Methodology: RS NWC SN GDB.

                • Project administration: TC ADB.

                • Resources: JB KH.

                • Supervision: ADB.

                • Visualization: RS NWC.

                • Writing – original draft: RS NWC TC ADB.

                • Writing – review & editing: RS NWC SN GDB TC JB KH ADB.

                Article
                PONE-D-16-46572
                10.1371/journal.pone.0179327
                5476266
                28628632
                © 2017 Sampath et al

                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: 0, Pages: 20
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01 AI110173
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: KL2 TR000136
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: R01 AI120698
                Award Recipient :
                This publication was made possible by CTSA Grant Number KL2 TR000136 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH); grant numbers R01 AI110173 and R01 AI120698 from the National Institute of Allergy and Infectious Diseases; and by funding from the Division of Infectious Diseases, Mayo Clinic Rochester and the Minneapolis Medical Research Foundation (MMRF). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of NIH, Mayo Clinic or University of Minnesota.
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                Custom metadata
                All relevant data are within the paper, with the exception of the results of the caspase 8 ELISA drug screen. This data is archived on Dryad at http://datadryad.org/review?doi=doi:10.5061/dryad.19fg1.

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