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Title: Modeling the effects of vorinostat in vivo reveals both transient and delayed HIV transcriptional activation and minimal killing of latently infected cells

Recent efforts to cure human immunodeficiency virus type-1 (HIV-1) infection have focused on developing latency reversing agents as a first step to eradicate the latent reservoir. The histone deacetylase inhibitor, vorinostat, has been shown to activate HIV RNA transcription in CD4+ T-cells and alter host cell gene transcription in HIV-infected individuals on antiretroviral therapy. In order to understand how latently infected cells respond dynamically to vorinostat treatment and determine the impact of vorinostat on reservoir size in vivo, we have constructed viral dynamic models of latency that incorporate vorinostat treatment. We fitted these models to data collected from a recent clinical trial in which vorinostat was administered daily for 14 days to HIV-infected individuals on suppressive ART. The results show that HIV transcription is increased transiently during the first few hours or days of treatment and that there is a delay before a sustained increase of HIV transcription, whose duration varies among study participants and may depend on the long term impact of vorinostat on host gene expression. Parameter estimation suggests that in latently infected cells, HIV transcription induced by vorinostat occurs at lower levels than in productively infected cells. Lastly, the estimated loss rate of transcriptionally induced cells remainsmore » close to baseline in most study participants, suggesting vorinostat treatment does not induce latently infected cell killing and thus reduce the latent reservoir in vivo.« less
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [5]
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); North Carolina State Univ., Raleigh, NC (United States)
  2. The Univ. of Melbourne, Melbourne (Australia); Alfred Hospital and Monash Univ., Melbourne (Australia); Burnet Institute, Melbourne (Australia)
  3. Alfred Hospital and Monash Univ., Melbourne (Australia)
  4. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  5. Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
Publication Date:
OSTI Identifier:
1235937
Report Number(s):
LA-UR--15-23220
Journal ID: ISSN 1553-7374
Grant/Contract Number:
AC52-06NA25396
Type:
Accepted Manuscript
Journal Name:
PLoS Pathogens
Additional Journal Information:
Journal Volume: 11; Journal Issue: 10; Journal ID: ISSN 1553-7374
Publisher:
Public Library of Science
Research Org:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES HIV; DNA transcription; cell death; gene expression; HIV infections; gene regulation; T cells; virions