Dysregulation of endoplasmic reticulum stress and autophagic responses by the antiretroviral drug efavirenz

Luc Bertrand, Michal J Toborek

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Increasing evidence demonstrates that the antiretroviral drugs (ARVds) used for human immunodeficiency virus (HIV) treatment have toxic effects that result in various cellular and tissue pathologies; however, their impact on the cells composing the blood-brain barrier is poorly understood. The current study focused on ARVds, used either in combination or alone, on the induction of endoplasmic reticulum (ER) stress responses in human brain endothelial cells. Among studied drugs (efavirenz, tenofovir, emtricitabine, lamivudine, and indinavir), only efavirenz increased ER stress via upregulation and activation of protein kinase-like ER kinase PERK and inositol requiring kinase 1α (IRE1α). At the same time, efavirenz diminished autophagic activity, a surprising result because typically the induction of ER stress is linked to enhanced autophagy. These results were confirmed in microvessels of HIV transgenic mice chronically administered with efavirenz. In a series of further experiments, we identified that efavirenz dysregulated ER stress and autophagy by blocking the activity of the Beclin-1/Atg14/PI3KIII complex in regard to synthesis of phosphatidylinositol 3-phosphate, a process that is linked to the formation of autophagosomes. Because autophagy is a protective mechanism involved in the removal of dysfunctional proteins and organelles, its inhibition can contribute to the toxicity of efavirenz or the development of neurodegenerative disease in HIV patients treated with this drug.

Original languageEnglish (US)
Pages (from-to)304-315
Number of pages12
JournalMolecular Pharmacology
Volume88
Issue number2
DOIs
StatePublished - Aug 1 2015

Fingerprint

efavirenz
Endoplasmic Reticulum Stress
Autophagy
Pharmaceutical Preparations
Tenofovir
HIV
Indinavir
Lamivudine
Poisons
Inositol
Microvessels
Blood-Brain Barrier
Endoplasmic Reticulum
Neurodegenerative Diseases
Organelles
Protein Kinases
Transgenic Mice
Phosphotransferases
Up-Regulation
Endothelial Cells

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Dysregulation of endoplasmic reticulum stress and autophagic responses by the antiretroviral drug efavirenz. / Bertrand, Luc; Toborek, Michal J.

In: Molecular Pharmacology, Vol. 88, No. 2, 01.08.2015, p. 304-315.

Research output: Contribution to journalArticle

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