Autophagy induction by histone deacetylase inhibitors inhibits HIV type 1

J Biol Chem. 2015 Feb 20;290(8):5028-40. doi: 10.1074/jbc.M114.605428. Epub 2014 Dec 24.

Abstract

Histone deacetylase inhibitors (HDACi) are being evaluated in a "shock-and-kill" therapeutic approach to reverse human immunodeficiency virus type-1 (HIV) latency from CD4(+) T cells. Using this approach, HDACi have induced HIV RNA synthesis in latently infected cells from some patients. The hope is that the increase in viral production will lead to killing of the infected cell either by the virus itself or by the patient's immune system, a "sterilizing cure." Although administered within the context of combination antiretroviral therapy, the infection of bystander cells remains a concern. In this study, we investigated the effect of HDACi (belinostat, givinostat, panobinostat, romidepsin, and vorinostat) on the productive infection of macrophages. We demonstrate that the HDACi tested do not alter the initial susceptibility of macrophages to HIV infection. However, we demonstrate that HDACi decrease HIV release from macrophages in a dose-dependent manner (belinostat < givinostat < vorinostat < panobinostat < romidepsin) via degradation of intracellular HIV through the canonical autophagy pathway. This mechanism involves unc-51-like autophagy-activating kinase 1 (ULK1) and the inhibition of the mammalian target of rapamycin and requires the formation of autophagosomes and their maturation into autolysosomes in the absence of increased cell death. These data provide further evidence in support of a role for autophagy in the control of HIV infection and suggest that careful consideration of off-target effects will be essential if HDACi are to be a component of a multipronged approach to eliminate latently infected cells.

Keywords: Autophagy Autophagy-related Protein 7 (ATG7); Histone Deacetylase Inhibitor (HDACi); Human Immunodeficiency Virus (HIV); Macrophage.

Publication types

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

MeSH terms

  • Autophagy / drug effects*
  • Autophagy-Related Protein-1 Homolog
  • Female
  • HIV Infections* / drug therapy
  • HIV Infections* / enzymology
  • HIV Infections* / pathology
  • HIV-1 / physiology*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lysosomes / pathology
  • Lysosomes / virology
  • Macrophages* / enzymology
  • Macrophages* / pathology
  • Macrophages* / virology
  • Male
  • Protein-Serine-Threonine Kinases / metabolism
  • TOR Serine-Threonine Kinases / metabolism
  • Virus Latency / drug effects*

Substances

  • Histone Deacetylase Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Autophagy-Related Protein-1 Homolog
  • Protein-Serine-Threonine Kinases
  • ULK1 protein, human