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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

Journal Article · · PLoS Pathogens
 [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)
+ Show Author Affiliations

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 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.

Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
USDOE
Grant/Contract Number:
AC52-06NA25396
OSTI ID:
1235937
Report Number(s):
LA-UR-15-23220
Journal Information:
PLoS Pathogens, Vol. 11, Issue 10; ISSN 1553-7374
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 35 works
Citation information provided by
Web of Science

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  • H., Woelk, Christopher; D., Garbis, Spiros; E., Johnston, Harvey
  • The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/7xdv-2w35
text January 2015
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Cited By (15)

Modeling HIV Dynamics Under Combination Therapy with Inducers and Antibodies journal June 2019
Histone deacetylases in monocyte/macrophage development, activation and metabolism: refining HDAC targets for inflammatory and infectious diseases journal January 2016
Hierarchical effects of pro-inflammatory cytokines on the post-influenza susceptibility to pneumococcal coinfection journal November 2016
Probabilistic control of HIV latency and transactivation by the Tat gene circuit journal November 2018
Ongoing Clinical Trials of Human Immunodeficiency Virus Latency-Reversing and Immunomodulatory Agents journal January 2016
Determinants of the efficacy of HIV latency-reversing agents and implications for drug and treatment design journal October 2018
What do we measure when we measure cell-associated HIV RNA journal January 2018
Epigenetics in Sepsis: Understanding Its Role in Endothelial Dysfunction, Immunosuppression, and Potential Therapeutics journal June 2019
Determinants of the efficacy of HIV latency-reversing agents and implications for drug and treatment design text January 2018
Interval dosing with the HDAC inhibitor vorinostat effectively reverses HIV latency text January 2017
Safety and Preliminary Efficacy of Vorinostat With R-EPOCH in High-risk HIV-associated Non-Hodgkin's Lymphoma (AMC-075) journal March 2018
Differences in Transcriptional Dynamics Between T-cells and Macrophages as Determined by a Three-State Mathematical Model journal February 2020
Predictions of time to HIV viral rebound following ART suspension that incorporate personal biomarkers journal July 2019
Have Cells Harboring the HIV Reservoir Been Immunoedited? journal August 2019
Mathematical Analysis of Viral Replication Dynamics and Antiviral Treatment Strategies: From Basic Models to Age-Based Multi-Scale Modeling journal July 2018

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
HIV
DNA transcription
cell death
gene expression
HIV infections
gene regulation
T cells
virions