SMAC Mimetics Induce Autophagy-Dependent Apoptosis of HIV-1-Infected Resting Memory CD4+ T Cells

Cell Host Microbe. 2018 Nov 14;24(5):689-702.e7. doi: 10.1016/j.chom.2018.09.007. Epub 2018 Oct 18.

Abstract

Long-lived resting memory CD4+ T cells (TCM) are a major reservoir of latent HIV infection. We hypothesized that latent HIV-TCM cells are maintained by aberrant expression of cell survival factors, including XIAP, BIRC2/cIAP1, and beclin-1. DIABLO/SMAC mimetics are therapeutic agents that compromise cell survival by hijacking host apoptotic machinery. We found that DIABLO/SMAC mimetics (birinapant, GDC-0152, and embelin) selectively kill HIV-TCM without increasing virus production or targeting uninfected TCM. Treatment of HIV-TCM with DIABLO/SMAC mimetics promoted XIAP and BIRC2 degradation, which triggered autophagy and the formation of a cell death complex consisting of pro-apoptotic (FADD, RIPK1, RIPK3, and caspase 8) and autophagy (ATG5, ATG7, and SQSTM1) proteins. Genetic or pharmacological inhibition of autophagy induction, but not autophagy-mediated degradation, abrogated this interaction and subsequent cell death. Our findings identify a mechanism whereby DIABLO/SMAC mimetics exploit autophagy and apoptotic machinery to selectively induce killing of HIV-TCM without viral reactivation while sparing uninfected cells.

Keywords: BIRC2; CD4+ T cell; Fas; HIV; RIPK1; SMAC mimetics; XIAP; apoptosis; autophagy; caspase 8.

Publication types

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

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • Autophagy / drug effects*
  • Autophagy / physiology*
  • Autophagy-Related Protein 5 / metabolism
  • Autophagy-Related Protein 7 / metabolism
  • Baculoviral IAP Repeat-Containing 3 Protein / metabolism
  • Beclin-1 / metabolism
  • Benzoquinones / pharmacology
  • CD4-Positive T-Lymphocytes / immunology*
  • Caspase 8 / metabolism
  • Cell Death
  • Cell Line
  • Cyclohexanes / pharmacology
  • Dipeptides / pharmacology
  • Fas-Associated Death Domain Protein / metabolism
  • HIV Infections / immunology*
  • HIV-1 / drug effects*
  • HIV-1 / pathogenicity
  • HIV-1 / physiology*
  • Humans
  • Indoles / pharmacology
  • Inhibitor of Apoptosis Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mitochondrial Proteins / metabolism
  • Pyrroles / pharmacology
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Sequestosome-1 Protein / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • X-Linked Inhibitor of Apoptosis Protein / metabolism

Substances

  • ATG5 protein, human
  • Apoptosis Regulatory Proteins
  • Autophagy-Related Protein 5
  • Beclin-1
  • Benzoquinones
  • Cyclohexanes
  • DIABLO protein, human
  • Dipeptides
  • FADD protein, human
  • Fas-Associated Death Domain Protein
  • Indoles
  • Inhibitor of Apoptosis Proteins
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Pyrroles
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • GDC-0152
  • birinapant
  • BIRC2 protein, human
  • BIRC3 protein, human
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Ubiquitin-Protein Ligases
  • RIPK1 protein, human
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Caspase 8
  • ATG7 protein, human
  • Autophagy-Related Protein 7
  • embelin