Histone deacetylase inhibitor romidepsin inhibits de novo HIV-1 infections

Antimicrob Agents Chemother. 2015 Jul;59(7):3984-94. doi: 10.1128/AAC.00574-15. Epub 2015 Apr 20.

Abstract

Adjunct therapy with the histone deacetylase inhibitor (HDACi) romidepsin increases plasma viremia in HIV patients on combination antiretroviral therapy (cART). However, a potential concern is that reversing HIV latency with an HDACi may reactivate the virus in anatomical compartments with suboptimal cART concentrations, leading to de novo infection of susceptible cells in these sites. We tested physiologically relevant romidepsin concentrations known to reactivate latent HIV in order to definitively address this concern. We found that romidepsin significantly inhibited HIV infection in peripheral blood mononuclear cells and CD4(+) T cells but not in monocyte-derived macrophages. In addition, romidepsin impaired HIV spreading in CD4(+) T cell cultures. When we evaluated the impact of romidepsin on quantitative viral outgrowth assays with primary resting CD4(+) T cells, we found that resting CD4(+) T cells exposed to romidepsin exhibited reduced proliferation and viability. This significantly lowered assay sensitivity when measuring the efficacy of romidepsin as an HIV latency reversal agent. Altogether, our data indicate that romidepsin-based HIV eradication strategies are unlikely to reseed a latent T cell reservoir, even under suboptimal cART conditions, because romidepsin profoundly restricts de novo HIV infections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology
  • CD4-Positive T-Lymphocytes / virology
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Depsipeptides / therapeutic use*
  • HIV Infections / drug therapy*
  • HIV Infections / virology
  • HIV-1*
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Humans
  • Interferon-gamma / pharmacology
  • Monocytes / virology
  • Primary Cell Culture
  • Virus Latency / drug effects
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Depsipeptides
  • Histone Deacetylase Inhibitors
  • Interferon-gamma
  • romidepsin