Induction of autophagy by PI3K/MTOR and PI3K/MTOR/BRD4 inhibitors suppresses HIV-1 replication

J Biol Chem. 2018 Apr 20;293(16):5808-5820. doi: 10.1074/jbc.RA118.002353. Epub 2018 Feb 23.


In this study, we investigated the effects of the dual phosphatidylinositol 3-kinase/mechanistic target of rapamycin (PI3K/MTOR) inhibitor dactolisib (NVP-BEZ235), the PI3K/MTOR/bromodomain-containing protein 4 (BRD4) inhibitor SF2523, and the bromodomain and extra terminal domain inhibitor JQ1 on the productive infection of primary macrophages with human immunodeficiency type-1 (HIV). These inhibitors did not alter the initial susceptibility of macrophages to HIV infection. However, dactolisib, JQ1, and SF2523 all decreased HIV replication in macrophages in a dose-dependent manner via degradation of intracellular HIV through autophagy. Macrophages treated with dactolisib, JQ1, or SF2523 displayed an increase in LC3B lipidation combined with SQSTM1 degradation without inducing increased cell death. LC3B-II levels were further increased in the presence of pepstatin A suggesting that these inhibitors induce autophagic flux. RNA interference for ATG5 and ATG7 and pharmacological inhibitors of autophagosome-lysosome fusion and of lysosomal hydrolases all blocked the inhibition of HIV. Thus, we demonstrate that the mechanism of PI3K/MTOR and PI3K/MTOR/BRD4 inhibitor suppression of HIV requires the formation of autophagosomes, as well as their subsequent maturation into autolysosomes. These data provide further evidence in support of a role for autophagy in the control of HIV infection and open new avenues for the use of this class of drugs in HIV therapy.

Keywords: JQ1; NVP-BEZ235; SF2523; autophagy; autophagy-related protein 7 (ATG7); human immunodeficiency virus (HIV); macrophage; phosphatidylinositol signaling.

Publication types

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

MeSH terms

  • Anti-HIV Agents / pharmacology*
  • Autophagy / drug effects*
  • Azepines / pharmacology*
  • Cell Cycle Proteins
  • Cells, Cultured
  • HIV Infections / drug therapy*
  • HIV Infections / metabolism
  • HIV Infections / pathology
  • HIV Infections / virology
  • HIV-1 / drug effects*
  • HIV-1 / physiology
  • Humans
  • Imidazoles / pharmacology*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / pathology
  • Macrophages / virology
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / metabolism
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors / pharmacology*
  • Quinolines / pharmacology*
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism
  • Triazoles / pharmacology*
  • Virus Replication / drug effects*


  • (+)-JQ1 compound
  • Anti-HIV Agents
  • Azepines
  • BRD4 protein, human
  • Cell Cycle Proteins
  • Imidazoles
  • Nuclear Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Quinolines
  • Transcription Factors
  • Triazoles
  • TOR Serine-Threonine Kinases
  • Phosphatidylinositol 3-Kinase
  • dactolisib