Epigenetic Metabolite Acetate Inhibits Class I/II Histone Deacetylases, Promotes Histone Acetylation, and Increases HIV-1 Integration in CD4 + T Cells

J Virol. 2017 Jul 27;91(16):e01943-16. doi: 10.1128/JVI.01943-16. Print 2017 Aug 15.

Abstract

In this study, we investigated the effect of acetate, the most concentrated short-chain fatty acid (SCFA) in the gut and bloodstream, on the susceptibility of primary human CD4+ T cells to HIV-1 infection. We report that HIV-1 replication is increased in CD3/CD28-costimulated CD4+ T cells upon acetate treatment. This enhancing effect correlates with increased expression of the early activation marker CD69 and impaired class I/II histone deacetylase (HDAC) activity. In addition, acetate enhances acetylation of histones H3 and H4 and augments HIV-1 integration into the genome of CD4+ T cells. Thus, we propose that upon antigen presentation, acetate influences class I/II HDAC activity that transforms condensed chromatin into a more relaxed structure. This event leads to a higher level of viral integration and enhanced HIV-1 production. In line with previous studies showing reactivation of latent HIV-1 by SCFAs, we provide evidence that acetate can also increase the susceptibility of primary human CD4+ T cells to productive HIV-1 infection.IMPORTANCE Alterations in the fecal microbiota and intestinal epithelial damage involved in the gastrointestinal disorder associated with HIV-1 infection result in microbial translocation that leads to disease progression and virus-related comorbidities. Indeed, notably via production of short-chain fatty acids, bacteria migrating from the lumen to the intestinal mucosa could influence HIV-1 replication by epigenetic regulatory mechanisms, such as histone acetylation. We demonstrate that acetate enhances virus production in primary human CD4+ T cells. Moreover, we report that acetate impairs class I/II histone deacetylase activity and increases integration of HIV-1 DNA into the host genome. Therefore, it can be postulated that bacterial metabolites such as acetate modulate HIV-1-mediated disease progression.

Keywords: CD4+ T cells; HIV-1; histone acetylation; histone deacetylases; integration; provirus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / metabolism*
  • Acetylation
  • Antigens, CD / analysis
  • Antigens, Differentiation, T-Lymphocyte / analysis
  • CD4-Positive T-Lymphocytes / chemistry
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / virology*
  • Cells, Cultured
  • HIV-1 / physiology*
  • Histone Deacetylase Inhibitors / metabolism*
  • Histones / metabolism*
  • Humans
  • Lectins, C-Type / analysis
  • Protein Processing, Post-Translational*
  • Virus Integration*
  • Virus Replication

Substances

  • Acetates
  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD69 antigen
  • Histone Deacetylase Inhibitors
  • Histones
  • Lectins, C-Type