Ex vivo analysis identifies effective HIV-1 latency-reversing drug combinations

J Clin Invest. 2015 May;125(5):1901-12. doi: 10.1172/JCI80142. Epub 2015 Mar 30.


Reversal of HIV-1 latency by small molecules is a potential cure strategy. This approach will likely require effective drug combinations to achieve high levels of latency reversal. Using resting CD4+ T cells (rCD4s) from infected individuals, we developed an experimental and theoretical framework to identify effective latency-reversing agent (LRA) combinations. Utilizing ex vivo assays for intracellular HIV-1 mRNA and virion production, we compared 2-drug combinations of leading candidate LRAs and identified multiple combinations that effectively reverse latency. We showed that protein kinase C agonists in combination with bromodomain inhibitor JQ1 or histone deacetylase inhibitors robustly induce HIV-1 transcription and virus production when directly compared with maximum reactivation by T cell activation. Using the Bliss independence model to quantitate combined drug effects, we demonstrated that these combinations synergize to induce HIV-1 transcription. This robust latency reversal occurred without release of proinflammatory cytokines by rCD4s. To extend the clinical utility of our findings, we applied a mathematical model that estimates in vivo changes in plasma HIV-1 RNA from ex vivo measurements of virus production. Our study reconciles diverse findings from previous studies, establishes a quantitative experimental approach to evaluate combinatorial LRA efficacy, and presents a model to predict in vivo responses to LRAs.

Publication types

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

MeSH terms

  • Adult
  • Anti-HIV Agents / administration & dosage
  • Anti-HIV Agents / pharmacology*
  • Anti-HIV Agents / therapeutic use
  • Azepines / pharmacology*
  • Bryostatins / pharmacology*
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology*
  • Cells, Cultured
  • Disulfiram / pharmacology*
  • Drug Evaluation, Preclinical
  • Drug Synergism
  • Female
  • HIV Infections / drug therapy
  • HIV Infections / virology
  • HIV-1 / drug effects*
  • HIV-1 / physiology
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Lymphocyte Activation
  • Lymphokines / metabolism
  • Male
  • Middle Aged
  • Phorbol Esters / pharmacology
  • Protein Kinase C / drug effects
  • RNA, Messenger / analysis
  • RNA, Viral / analysis
  • Transcription, Genetic / drug effects
  • Triazoles / pharmacology*
  • Virion / metabolism
  • Virus Latency / drug effects*


  • (+)-JQ1 compound
  • Anti-HIV Agents
  • Azepines
  • Bryostatins
  • Histone Deacetylase Inhibitors
  • Lymphokines
  • Phorbol Esters
  • RNA, Messenger
  • RNA, Viral
  • Triazoles
  • bryostatin 1
  • prostratin
  • Protein Kinase C
  • Disulfiram