Sulfonation pathway inhibitors block reactivation of latent HIV-1

Virology. 2014 Dec;471-473:1-12. doi: 10.1016/j.virol.2014.08.016. Epub 2014 Oct 11.

Abstract

Long-lived pools of latently infected cells are a significant barrier to the development of a cure for HIV-1 infection. A better understanding of the mechanisms of reactivation from latency is needed to facilitate the development of novel therapies that address this problem. Here we show that chemical inhibitors of the sulfonation pathway prevent virus reactivation, both in latently infected J-Lat and U1 cell lines and in a primary human CD4+ T cell model of latency. In each of these models, sulfonation inhibitors decreased transcription initiation from the HIV-1 promoter. These inhibitors block transcription initiation at a step that lies downstream of nucleosome remodeling and affects RNA polymerase II recruitment to the viral promoter. These results suggest that the sulfonation pathway acts by a novel mechanism to regulate efficient virus transcription initiation during reactivation from latency, and further that augmentation of this pathway could be therapeutically useful.

Keywords: Gene expression; HIV-1; Inhibitor; Latency; Primary CD4+ T cells; Reactivation; Sulfonation.

Publication types

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

MeSH terms

  • Anti-HIV Agents / administration & dosage
  • Anti-HIV Agents / pharmacology*
  • CD4-Positive T-Lymphocytes / virology
  • Cell Line
  • Chlorates / administration & dosage
  • Chlorates / pharmacology*
  • Drug Therapy, Combination
  • Gene Expression Regulation, Viral / physiology
  • Guaiacol / administration & dosage
  • Guaiacol / pharmacology*
  • HIV Long Terminal Repeat
  • HIV-1 / drug effects*
  • HIV-1 / metabolism
  • Humans
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • RNA Polymerase II / metabolism
  • Sulfonic Acids / antagonists & inhibitors
  • Sulfonic Acids / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Virus Activation / drug effects*
  • Virus Latency / physiology

Substances

  • Anti-HIV Agents
  • Chlorates
  • NF-kappa B
  • Sulfonic Acids
  • Tumor Necrosis Factor-alpha
  • Guaiacol
  • RNA Polymerase II