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

Nat Med. 2014 Apr;20(4):425-9. doi: 10.1038/nm.3489. Epub 2014 Mar 23.


HIV-1 persists in a latent reservoir despite antiretroviral therapy (ART). This reservoir is the major barrier to HIV-1 eradication. Current approaches to purging the latent reservoir involve pharmacologic induction of HIV-1 transcription and subsequent killing of infected cells by cytolytic T lymphocytes (CTLs) or viral cytopathic effects. Agents that reverse latency without activating T cells have been identified using in vitro models of latency. However, their effects on latently infected cells from infected individuals remain largely unknown. Using a new ex vivo assay, we demonstrate that none of the latency-reversing agents (LRAs) tested induced outgrowth of HIV-1 from the latent reservoir of patients on ART. Using a quantitative reverse transcription PCR assay specific for all HIV-1 mRNAs, we demonstrate that LRAs that do not cause T cell activation do not induce substantial increases in intracellular HIV-1 mRNA in patient cells; only the protein kinase C agonist bryostatin-1 caused significant increases. These findings demonstrate that current in vitro models do not fully recapitulate mechanisms governing HIV-1 latency in vivo. Further, our data indicate that non-activating LRAs are unlikely to drive the elimination of the latent reservoir in vivo when administered individually.

Publication types

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

MeSH terms

  • Anti-HIV Agents / pharmacology*
  • Azepines / pharmacology
  • Bryostatins / pharmacology
  • CD4-Positive T-Lymphocytes / drug effects*
  • Cell Cycle Proteins
  • Depsipeptides / pharmacology
  • Disulfiram / pharmacology
  • HIV Infections / drug therapy*
  • HIV-1 / drug effects*
  • HIV-1 / physiology
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Hydroxamic Acids / pharmacology
  • Indoles / pharmacology
  • Ionomycin / pharmacology
  • Lymphocyte Activation
  • Nuclear Proteins / antagonists & inhibitors
  • Panobinostat
  • Tetradecanoylphorbol Acetate / pharmacology*
  • Transcription Factors / antagonists & inhibitors
  • Triazoles / pharmacology
  • Virus Latency / drug effects*
  • Virus Latency / immunology
  • Vorinostat


  • (+)-JQ1 compound
  • Anti-HIV Agents
  • Azepines
  • BRD4 protein, human
  • Bryostatins
  • Cell Cycle Proteins
  • Depsipeptides
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Indoles
  • Nuclear Proteins
  • Transcription Factors
  • Triazoles
  • bryostatin 1
  • Ionomycin
  • Vorinostat
  • Panobinostat
  • romidepsin
  • Tetradecanoylphorbol Acetate
  • Disulfiram