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Modeling the Effects of Vorinostat In Vivo Reveals both Transient and Delayed HIV Transcriptional Activation and Minimal Killing of Latently Infected Cells.

Ke R, Lewin SR, Elliott JH, Perelson AS
Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America; Department of Mathematics, North Carolina State University, Raleigh, North Carolina, United States of America.


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. Furthermore, the estimated loss rate of transcriptionally induced cells remains 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.


This work was performed under the auspices of the U.S. Department of Energy under contract DE-AC52-06NA25396 and supported by NIH grants R01-AI028433, R01-OD011095 and UM1- AI100645 (ASP). SRL is an NHMRC Practitioner Fellow. This work was also supported by NHMRC project grants # 4911954 and #1002671 and the National Institutes of Health Delaney AIDS Research Enterprise (DARE) to find a cure U19 AI096109. The clinical study of vorinostat was supported in part by a research grant from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp. The authors gratefully acknowledge the contribution to this work of the Victorian Operational Infrastructure Support Program received by the Burnet Institute.


  • Journal: PLoS Pathogens
  • Published: 01/10/2015
  • Volume: 11
  • Issue: 10
  • Pagination: e1005237


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