skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

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

Abstract

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:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1235937
Report Number(s):
LA-UR-15-23220
Journal ID: ISSN 1553-7374
Grant/Contract Number:  
AC52-06NA25396
Resource 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
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

Citation Formats

Ke, Ruian, Lewin, Sharon R., Elliott, Julian H., Perelson, Alan S., and Chakraborty, Arup K. Modeling the effects of vorinostat in vivo reveals both transient and delayed HIV transcriptional activation and minimal killing of latently infected cells. United States: N. p., 2015. Web. doi:10.1371/journal.ppat.1005237.
Ke, Ruian, Lewin, Sharon R., Elliott, Julian H., Perelson, Alan S., & Chakraborty, Arup K. Modeling the effects of vorinostat in vivo reveals both transient and delayed HIV transcriptional activation and minimal killing of latently infected cells. United States. doi:10.1371/journal.ppat.1005237.
Ke, Ruian, Lewin, Sharon R., Elliott, Julian H., Perelson, Alan S., and Chakraborty, Arup K. Fri . "Modeling the effects of vorinostat in vivo reveals both transient and delayed HIV transcriptional activation and minimal killing of latently infected cells". United States. doi:10.1371/journal.ppat.1005237. https://www.osti.gov/servlets/purl/1235937.
@article{osti_1235937,
title = {Modeling the effects of vorinostat in vivo reveals both transient and delayed HIV transcriptional activation and minimal killing of latently infected cells},
author = {Ke, Ruian and Lewin, Sharon R. and Elliott, Julian H. and Perelson, Alan S. and Chakraborty, Arup K.},
abstractNote = {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.},
doi = {10.1371/journal.ppat.1005237},
journal = {PLoS Pathogens},
number = 10,
volume = 11,
place = {United States},
year = {2015},
month = {10}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 10 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Declining Morbidity and Mortality among Patients with Advanced Human Immunodeficiency Virus Infection
journal, March 1998

  • Palella, Frank J.; Delaney, Kathleen M.; Moorman, Anne C.
  • New England Journal of Medicine, Vol. 338, Issue 13
  • DOI: 10.1056/NEJM199803263381301

The role of HIV in serious diseases other than AIDS
journal, January 2008


The Challenge of Finding a Cure for HIV Infection
journal, March 2009


Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells
journal, May 2003

  • Siliciano, Janet D.; Kajdas, Joleen; Finzi, Diana
  • Nature Medicine, Vol. 9, Issue 6
  • DOI: 10.1038/nm880

Shock and kill
journal, July 2012


Transcriptional activation and chromatin remodeling of the HIV-1 promoter in response to histone acetylation.
journal, March 1996


Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors
journal, February 2005

  • Peart, M. J.; Smyth, G. K.; van Laar, R. K.
  • Proceedings of the National Academy of Sciences, Vol. 102, Issue 10
  • DOI: 10.1073/pnas.0500369102

FDA Approval Summary: Vorinostat for Treatment of Advanced Primary Cutaneous T-Cell Lymphoma
journal, October 2007


Activation of HIV Transcription with Short-Course Vorinostat in HIV-Infected Patients on Suppressive Antiretroviral Therapy
journal, November 2014


Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy
journal, July 2012

  • Archin, N. M.; Liberty, A. L.; Kashuba, A. D.
  • Nature, Vol. 487, Issue 7408
  • DOI: 10.1038/nature11286

Mathematical Analysis of HIV-1 Dynamics in Vivo
journal, January 1999


HIV-1 Dynamics in Vivo: Virion Clearance Rate, Infected Cell Life-Span, and Viral Generation Time
journal, March 1996


Modeling HIV persistence, the latent reservoir, and viral blips
journal, September 2009


Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1
journal, August 2014

  • Hill, Alison L.; Rosenbloom, Daniel I. S.; Fu, Feng
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 37
  • DOI: 10.1073/pnas.1406663111

Modeling the Timing of Antilatency Drug Administration during HIV Treatment
journal, September 2014

  • Petravic, J.; Martyushev, A.; Reece, J. C.
  • Journal of Virology, Vol. 88, Issue 24
  • DOI: 10.1128/JVI.01701-14

Dynamics of HIV Latency and Reactivation in a Primary CD4+ T Cell Model
journal, May 2014


Quantification of HIV-1 latency reversal in resting CD4+ T cells from patients on suppressive antiretroviral therapy
journal, March 2014

  • Cillo, A. R.; Sobolewski, M. D.; Bosch, R. J.
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 19
  • DOI: 10.1073/pnas.1402873111

Replication-Competent Noninduced Proviruses in the Latent Reservoir Increase Barrier to HIV-1 Cure
journal, October 2013


Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection
journal, May 1997

  • Chun, Tae-Wook; Carruth, Lucy; Finzi, Diana
  • Nature, Vol. 387, Issue 6629
  • DOI: 10.1038/387183a0

Rapid Turnover of T Lymphocytes in SIV-Infected Rhesus Macaques
journal, February 1998


Dynamics of HIV infection of CD4+ T cells
journal, March 1993


Transient Viremia, Plasma Viral Load, and Reservoir Replenishment in HIV-Infected Patients on Antiretroviral Therapy
journal, January 2007

  • Jones, Laura E.; Perelson, Alan S.
  • JAIDS Journal of Acquired Immune Deficiency Syndromes, Vol. 45, Issue 5
  • DOI: 10.1097/QAI.0b013e3180654836

Robust Growth of Human Immunodeficiency Virus Type 1 (HIV-1)
journal, October 2005


Rev and the fate of pre-mRNA in the nucleus: implications for the regulation of RNA processing in eukaryotes.
journal, October 1993


In vitro RNA-RNA splicing in adenovirus 2 mRNA formation.
journal, November 1978

  • Blanchard, J. M.; Weber, J.; Jelinek, W.
  • Proceedings of the National Academy of Sciences, Vol. 75, Issue 11
  • DOI: 10.1073/pnas.75.11.5344

Constant Mean Viral Copy Number per Infected Cell in Tissues Regardless of High, Low, or Undetectable Plasma HIV RNA
journal, May 1999

  • Hockett, Richard D.; Michael Kilby, J.; Derdeyn, Cynthia A.
  • The Journal of Experimental Medicine, Vol. 189, Issue 10
  • DOI: 10.1084/jem.189.10.1545

Determination of virus burst size in vivo using a single-cycle SIV in rhesus macaques
journal, November 2007

  • Chen, H. Y.; Di Mascio, M.; Perelson, A. S.
  • Proceedings of the National Academy of Sciences, Vol. 104, Issue 48
  • DOI: 10.1073/pnas.0707449104

Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis
journal, November 1999


A Hardwired HIV Latency Program
journal, February 2015


Transient-mediated fate determination in a transcriptional circuit of HIV
journal, March 2008

  • Weinberger, Leor S.; Dar, Roy D.; Simpson, Michael L.
  • Nature Genetics, Vol. 40, Issue 4
  • DOI: 10.1038/ng.116

Stochastic Gene Expression in a Lentiviral Positive-Feedback Loop: HIV-1 Tat Fluctuations Drive Phenotypic Diversity
journal, July 2005


Control of Stochastic Gene Expression by Host Factors at the HIV Promoter
journal, January 2009


SIRT1 Regulates HIV Transcription via Tat Deacetylation
journal, February 2005


Duration of Nuclear NF-kappa B Action Regulated by Reversible Acetylation
journal, August 2001


NF-κB Binds P-TEFb to Stimulate Transcriptional Elongation by RNA Polymerase II
journal, August 2001


Cyclin T1 and CDK9 T-Loop Phosphorylation Are Downregulated during Establishment of HIV-1 Latency in Primary Resting Memory CD4+ T Cells
journal, November 2012

  • Budhiraja, S.; Famiglietti, M.; Bosque, A.
  • Journal of Virology, Vol. 87, Issue 2
  • DOI: 10.1128/JVI.02413-12

Histone Deacetylase Inhibitors (HDACis) That Release the Positive Transcription Elongation Factor b (P-TEFb) from Its Inhibitory Complex Also Activate HIV Transcription
journal, March 2013

  • Bartholomeeusen, Koen; Fujinaga, Koh; Xiang, Yanhui
  • Journal of Biological Chemistry, Vol. 288, Issue 20
  • DOI: 10.1074/jbc.M113.464834

Basal shuttle of NF-κB/IκBα in resting T lymphocytes regulates HIV-1 LTR dependent expression
journal, January 2007

  • Coiras, Mayte; López-Huertas, María; Rullas, Joaquín
  • Retrovirology, Vol. 4, Issue 1
  • DOI: 10.1186/1742-4690-4-56

The gene product Murr1 restricts HIV-1 replication in resting CD4+ lymphocytes
journal, December 2003

  • Ganesh, Lakshmanan; Burstein, Ezra; Guha-Niyogi, Anuradha
  • Nature, Vol. 426, Issue 6968
  • DOI: 10.1038/nature02171

Caught in translation: innate restriction of HIV mRNA translation by a schlafen family protein
journal, November 2012

  • Jakobsen, Martin R.; Mogensen, Trine H.; Paludan, Søren R.
  • Cell Research, Vol. 23, Issue 3
  • DOI: 10.1038/cr.2012.155

Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu
journal, January 2008

  • Neil, Stuart J. D.; Zang, Trinity; Bieniasz, Paul D.
  • Nature, Vol. 451, Issue 7177
  • DOI: 10.1038/nature06553

Influence of delayed viral production on viral dynamics in HIV-1 infected patients
journal, September 1998


Viral and Latent Reservoir Persistence in HIV-1–Infected Patients on Therapy
journal, January 2006


HIV-1 Expression Within Resting CD4+ T Cells After Multiple Doses of Vorinostat
journal, March 2014

  • Archin, N. M.; Bateson, R.; Tripathy, M. K.
  • Journal of Infectious Diseases, Vol. 210, Issue 5
  • DOI: 10.1093/infdis/jiu155

New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo
journal, March 2014

  • Bullen, C. Korin; Laird, Gregory M.; Durand, Christine M.
  • Nature Medicine, Vol. 20, Issue 4
  • DOI: 10.1038/nm.3489

Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection
journal, May 2012

  • Archin, N. M.; Vaidya, N. K.; Kuruc, J. D.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 24
  • DOI: 10.1073/pnas.1120248109

The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo
journal, September 2015


Density-Dependent Decay in HIV-1 Dynamics
journal, January 2006


HIV-1 Infection and Low Steady State Viral Loads
journal, January 2002


A Stochastic Model of Latently Infected Cell Reactivation and Viral Blip Generation in Treated HIV Patients
journal, April 2011


Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy
journal, May 1999

  • Finzi, Diana; Blankson, Joel; Siliciano, Janet D.
  • Nature Medicine, Vol. 5, Issue 5
  • DOI: 10.1038/8394

Human immunodeficiency virus type 1 transactivator protein, tat, stimulates transcriptional read-through of distal terminator sequences in vitro.
journal, July 1993

  • Graeble, M. A.; Churcher, M. J.; Lowe, A. D.
  • Proceedings of the National Academy of Sciences, Vol. 90, Issue 13
  • DOI: 10.1073/pnas.90.13.6184

A Simplex Method for Function Minimization
journal, January 1965


    Works referencing / citing this record:

    Modeling HIV Dynamics Under Combination Therapy with Inducers and Antibodies
    journal, June 2019