Skip to main content
OSTI.GOVU.S. Department of Energy Office of Scientific and Technical Information
U.S. Department of Energy
Office of Scientific and Technical Information
 

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, Journal Name: PLoS Pathogens Journal Issue: 10 Vol. 11; ISSN 1553-7374
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

References (84)

Transcriptional activation and chromatin remodeling of the HIV-1 promoter in response to histone acetylation. journal March 1996
HIV-1 Infection and Low Steady State Viral Loads journal January 2002
Dynamics of HIV infection of CD4+ T cells journal March 1993
Mixed effects of suberoylanilide hydroxamic acid (SAHA) on the host transcriptome and proteome and their implications for HIV reactivation from latency journal November 2015
And the Noise Played on: Stochastic Gene Expression and HIV-1 Infection journal July 2005
Replication-Competent Noninduced Proviruses in the Latent Reservoir Increase Barrier to HIV-1 Cure journal October 2013
A Hardwired HIV Latency Program journal February 2015
Modeling HIV persistence, the latent reservoir, and viral blips journal September 2009
Asymmetric division of activated latently infected cells may explain the decay kinetics of the HIV-1 latent reservoir and intermittent viral blips journal January 2009
Influence of delayed viral production on viral dynamics in HIV-1 infected patients journal September 1998
Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis journal November 1999
NF-κB Binds P-TEFb to Stimulate Transcriptional Elongation by RNA Polymerase II journal August 2001
Tentative first steps to eradicate latent HIV journal October 2014
Caught in translation: innate restriction of HIV mRNA translation by a schlafen family protein journal November 2012
The gene product Murr1 restricts HIV-1 replication in resting CD4+ lymphocytes journal December 2003
Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu journal January 2008
Transient-mediated fate determination in a transcriptional circuit of HIV journal March 2008
Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells journal May 2003
Determination of virus burst size in vivo using a single-cycle SIV in rhesus macaques journal November 2007
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
Constant Mean Viral Copy Number per Infected Cell in Tissues Regardless of High, Low, or Undetectable Plasma HIV RNA journal May 1999
Effect of Histone Deacetylase Inhibitors on HIV Production in Latently Infected, Resting CD4+ T Cells From Infected Individuals Receiving Effective Antiretroviral Therapy journal June 2012
Density-Dependent Decay in HIV-1 Dynamics journal January 2006
The role of HIV in serious diseases other than AIDS journal January 2008
Transient Viremia, Plasma Viral Load, and Reservoir Replenishment in HIV-Infected Patients on Antiretroviral Therapy journal January 2007
Duration of Nuclear NF-kappa B Action Regulated by Reversible Acetylation journal August 2001
The Challenge of Finding a Cure for HIV Infection journal March 2009
Rapid Turnover of T Lymphocytes in SIV-Infected Rhesus Macaques journal February 1998
Modeling the Timing of Antilatency Drug Administration during HIV Treatment journal September 2014
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
A Novel Antiviral Intervention Results in More Accurate Assessment of Human Immunodeficiency Virus Type 1 Replication Dynamics and T-Cell Decay In Vivo journal April 2003
Rev and the fate of pre-mRNA in the nucleus: implications for the regulation of RNA processing in eukaryotes. journal October 1993
Basal shuttle of NF-κB/IκBα in resting T lymphocytes regulates HIV-1 LTR dependent expression journal January 2007
Modeling Latently Infected Cell Activation: Viral and Latent Reservoir Persistence, and Viral Blips in HIV-infected Patients on Potent Therapy journal October 2009
A Stochastic Model of Latently Infected Cell Reactivation and Viral Blip Generation in Treated HIV Patients journal April 2011
Control of Stochastic Gene Expression by Host Factors at the HIV Promoter journal January 2009
Dynamics of HIV Latency and Reactivation in a Primary CD4+ T Cell Model journal May 2014
Activation of HIV Transcription with Short-Course Vorinostat in HIV-Infected Patients on Suppressive Antiretroviral Therapy journal November 2014
The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo journal September 2015
Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1 text January 2014
Dynamics of HIV infection of CD4+ T cells journal March 1993
Influence of delayed viral production on viral dynamics in HIV-1 infected patients journal September 1998
Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis journal November 1999
NF-κB Binds P-TEFb to Stimulate Transcriptional Elongation by RNA Polymerase II journal August 2001
Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial journal October 2014
Stochastic Gene Expression in a Lentiviral Positive-Feedback Loop: HIV-1 Tat Fluctuations Drive Phenotypic Diversity journal July 2005
Stimulation of HIV-1-Specific Cytolytic T Lymphocytes Facilitates Elimination of Latent Viral Reservoir after Virus Reactivation journal March 2012
Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection journal May 1997
Shock and kill journal July 2012
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
Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy journal July 2012
New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo journal March 2014
Transient-mediated fate determination in a transcriptional circuit of HIV journal October 2007
Declining Morbidity and Mortality among Patients with Advanced Human Immunodeficiency Virus Infection journal March 1998
Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors journal February 2005
Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection journal May 2012
Quantification of HIV-1 latency reversal in resting CD4+ T cells from patients on suppressive antiretroviral therapy journal March 2014
Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1 journal August 2014
In vitro RNA-RNA splicing in adenovirus 2 mRNA formation. journal November 1978
Human immunodeficiency virus type 1 transactivator protein, tat, stimulates transcriptional read-through of distal terminator sequences in vitro. journal July 1993
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
A Simplex Method for Function Minimization journal January 1965
HIV-1 Expression Within Resting CD4+ T Cells After Multiple Doses of Vorinostat journal March 2014
The role of HIV in serious diseases other than AIDS journal January 2008
Transient Viremia, Plasma Viral Load, and Reservoir Replenishment in HIV-Infected Patients on Antiretroviral Therapy journal January 2007
HIV-1 Dynamics in Vivo: Virion Clearance Rate, Infected Cell Life-Span, and Viral Generation Time journal March 1996
Modeling the Timing of Antilatency Drug Administration during HIV Treatment journal September 2014
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
Repression of human immunodeficiency virus type 1 through the novel cooperation of human factors YY1 and LSF. journal January 1997
A Novel Antiviral Intervention Results in More Accurate Assessment of Human Immunodeficiency Virus Type 1 Replication Dynamics and T-Cell Decay In Vivo journal April 2003
Rev and the fate of pre-mRNA in the nucleus: implications for the regulation of RNA processing in eukaryotes. journal October 1993
Rev and the fate of pre-mRNA in the nucleus: implications for the regulation of RNA processing in eukaryotes journal October 1993
Mathematical Analysis of HIV-1 Dynamics in Vivo journal January 1999
SIRT1 Regulates HIV Transcription via Tat Deacetylation journal February 2005
Viral and Latent Reservoir Persistence in HIV-1–Infected Patients on Therapy journal January 2006
Viral and Latent Reservoir Persistence in HIV-1 Infected Patients on Therapy journal January 2005
Robust Growth of Human Immunodeficiency Virus Type 1 (HIV-1) journal October 2005
FDA Approval Summary: Vorinostat for Treatment of Advanced Primary Cutaneous T-Cell Lymphoma journal October 2007
Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy text January 2012
Immediate antiviral therapy appears to restrict resting CD4 + cell HIV-1 infection without accelerating the decay of latent infection text January 2012
Mixed effects of suberoylanilide hydroxamic acid (SAHA) on the host transcriptome and proteome and their implications for HIV reactivation from latency
  • 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
Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection text January 2012
HIV-1 Expression Within Resting CD4+ T Cells After Multiple Doses of Vorinostat text January 2014
Dynamics of HIV Latency and Reactivation in a Primary CD4+T Cell Model text January 2014

Cited By (16)

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
Ongoing Clinical Trials of Human Immunodeficiency Virus Latency-Reversing and Immunomodulatory Agents journal January 2016
What do we measure when we measure cell-associated HIV RNA journal January 2018
Predictions of time to HIV viral rebound following ART suspension that incorporate personal biomarkers journal July 2019
Epigenetics in Sepsis: Understanding Its Role in Endothelial Dysfunction, Immunosuppression, and Potential Therapeutics journal June 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
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
Determinants of the efficacy of HIV latency-reversing agents and implications for drug and treatment design journal October 2018
Interval dosing with the HDAC inhibitor vorinostat effectively reverses HIV latency journal July 2017
Interval dosing with the HDAC inhibitor vorinostat effectively reverses HIV latency text January 2017
Determinants of the efficacy of HIV latency-reversing agents and implications for drug and treatment design text January 2018

Similar Records

Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells
Journal Article · Sat Nov 14 23:00:00 EST 2015 · Virology · OSTI ID:22581645
TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy
Journal Article · Tue May 01 20:00:00 EDT 2018 · Science Translational Medicine · OSTI ID:1438143
Immunological Correlates of the HIV-1 Replication-Competent Reservoir Size
Journal Article · Sun Jun 27 20:00:00 EDT 2021 · Clinical Infectious Diseases · OSTI ID:1833261

Related Subjects

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