Administration of Vorinostat Disrupts HIV-1 Latency in Patients on Antiretroviral Therapy

Nature. 2012 Jul 25;487(7408):482-5. doi: 10.1038/nature11286.

Abstract

Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection. Inducing the expression of latent genomes within resting CD4(+) T cells is the primary strategy to clear this reservoir. Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro, the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Here we isolated the circulating resting CD4(+) T cells of patients in whom viraemia was fully suppressed by antiretroviral therapy, and directly studied the effect of VOR on this latent reservoir. In each of eight patients, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4(+) cells (mean increase, 4.8-fold). This demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly.

Trial registration: ClinicalTrials.gov NCT01319383.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation / drug effects
  • Anti-HIV Agents / therapeutic use*
  • Biomarkers / metabolism
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology
  • Gene Expression Regulation, Viral / drug effects
  • HIV Infections / blood
  • HIV Infections / drug therapy*
  • HIV Infections / virology*
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • HIV-1 / growth & development*
  • Histone Deacetylase Inhibitors / administration & dosage
  • Histone Deacetylase Inhibitors / adverse effects
  • Histone Deacetylase Inhibitors / pharmacology
  • Histones / drug effects
  • Histones / metabolism
  • Humans
  • Hydroxamic Acids / administration & dosage
  • Hydroxamic Acids / adverse effects
  • Hydroxamic Acids / pharmacology*
  • Proviruses / drug effects
  • Proviruses / genetics
  • Proviruses / growth & development
  • RNA, Viral / biosynthesis
  • RNA, Viral / blood
  • Risk Assessment
  • Up-Regulation / drug effects
  • Viremia / drug therapy
  • Viremia / virology
  • Virus Latency / drug effects*
  • Vorinostat

Substances

  • Anti-HIV Agents
  • Biomarkers
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • RNA, Viral
  • Vorinostat

Associated data

  • ClinicalTrials.gov/NCT01319383