Unique characteristics of histone deacetylase inhibitors in reactivation of latent HIV-1 in Bcl-2-transduced primary resting CD4+ Tcells

Liang Shan, Sifei Xing, Hung Chih Yang, Hao Zhang, Joseph B. Margolick, Robert F. Siliciano

Research output: Contribution to journalArticlepeer-review

Abstract

Objectives: The latent reservoir for HIV-1 in resting memory CD4+ T cells is a major barrier to eradication. In vitro models involving transformed cell lines have been used to search for small molecules that reactivate latent HIV-1. Histonedeacetylase(HDAC) inhibitors canreverse HIV-1 latent infection. MoststudiesonHDACinhibitors have been performed in cell line models that differ in important aspects fromthe resting CD4+Tcells that harbour latent HIV- 1 in vivo. Therefore, we evaluated the potency and kinetics of HDAC inhibitors in a primary cell model of HIV-1 latency that involves resting CD4+ T cells. Methods: A green fluorescent protein (GFP)-expressing reporter virus NL4-3-δ6-drGFPwas used to generate latent infection in Bcl-2-transduced primary CD4+ T cells. Seventeen HDAC inhibitors were tested in this primary cell model. The effects of these HDAC inhibitors on the reactivation of latent HIV-1 were determined and compared with anti-CD3 and anti-CD28 co-stimulation. Results: In Bcl-2-transduced primary CD4+ T cells, short-term treatment with HDAC inhibitors resulted in very limited reactivation of latent HIV-1, while prolonged treatment greatly enhanced drug efficacy. The effects of HDAC inhibitors in reactivating latent HIV-1 correlated with their inhibitory effects on class I HDACs. Importantly, HIV-1 reactivated by HDAC inhibitors can quickly re-establish latent infection upon drug removal. Conclusions:We identified unique features of HDAC inhibitor-induced reactivation of latent HIV-1 in primary CD4+ T cells. Our findings may be useful for the design of eradication trials.

Original languageEnglish (US)
Article numberdkt338
Pages (from-to)28-33
Number of pages6
JournalJournal of Antimicrobial Chemotherapy
Volume69
Issue number1
DOIs
StatePublished - Jan 2014

Keywords

  • Cytotoxicity
  • Latent reservoir
  • Vorinostat

ASJC Scopus subject areas

  • Pharmacology
  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

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