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      HDAC inhibition induces HIV-1 protein and enables immune-based clearance following latency reversal

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          Abstract

          Promising therapeutic approaches for eradicating HIV include transcriptional activation of provirus from latently infected cells using latency-reversing agents (LRAs) and immune-mediated clearance to purge reservoirs. Accurate detection of cells capable of producing viral antigens and virions, and the measurement of clearance of infected cells, is essential to assessing therapeutic efficacy. Here, we apply enhanced methodology extending the sensitivity limits for the rapid detection of subfemtomolar HIV gag p24 capsid protein in CD4 + T cells from ART-suppressed HIV + individuals, and we show viral protein induction following treatment with LRAs. Importantly, we demonstrate that clinical administration of histone deacetylase inhibitors (HDACis; vorinostat and panobinostat) induced HIV gag p24, and ex vivo stimulation produced sufficient viral antigen to elicit immune-mediated cell killing using anti-gp120/CD3 bispecific antibody. These findings extend beyond classical nucleic acid endpoints, which are confounded by the predominance of mutated, defective proviruses and, of paramount importance, enable assessment of cells making HIV protein that can now be targeted by immunological approaches.

          Abstract

          Clinical administration of HDAC inhibitors induces HIV protein expression and elicits immune-based clearance ex vivo.

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          Author and article information

          Contributors
          Journal
          JCI Insight
          JCI Insight
          JCI Insight
          JCI Insight
          American Society for Clinical Investigation
          2379-3708
          17 August 2017
          17 August 2017
          17 August 2017
          : 2
          : 16
          Affiliations
          [1 ]Department of Infectious Disease and
          [2 ]Department of Biologics and Vaccine Formulations, Merck & Co. Inc., Kenilworth, New Jersey, USA.
          [3 ]Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
          [4 ]Department of Biologics, Merck & Co. Inc., Kenilworth, New Jersey, USA.
          [5 ]Department of Infectious Diseases, Aarhus University Hospital, Aarhus N, Denmark.
          [6 ]University of North Carolina (UNC) HIV Cure Center, UNC Chapel Hill, Chapel Hill, North Carolina, USA.
          Author notes
          Address correspondence to: Bonnie J. Howell, Department of Infectious Disease, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. Phone: 215.652.2650; Email: bonnie_howell@ 123456merck.com .
          Article
          PMC5621903 PMC5621903 5621903 92901
          10.1172/jci.insight.92901
          5621903
          28814661
          a3fce0b1-1996-4589-a419-a0d077503cd4
          Copyright © 2017, American Society for Clinical Investigation
          Categories
          Research Article

          AIDS/HIV, Infectious disease

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