An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response

Proc Natl Acad Sci U S A. 2016 Jan 12;113(2):E117-26. doi: 10.1073/pnas.1514076113. Epub 2015 Dec 29.


Inhibitors of the HIV aspartyl protease [HIV protease inhibitors (HIV-PIs)] are the cornerstone of treatment for HIV. Beyond their well-defined antiretroviral activity, these drugs have additional effects that modulate cell viability and homeostasis. However, little is known about the virus-independent pathways engaged by these molecules. Here we show that the HIV-PI Nelfinavir decreases translation rates and promotes a transcriptional program characteristic of the integrated stress response (ISR). Mice treated with Nelfinavir display hallmarks of this stress response in the liver, including α subunit of translation initiation factor 2 (eIF2α) phosphorylation, activating transcription factor-4 (ATF4) induction, and increased expression of known downstream targets. Mechanistically, Nelfinavir-mediated ISR bypassed direct activation of the eIF2α stress kinases and instead relied on the inhibition of the constitutive eIF2α dephosphorylation and down-regulation of the phophatase cofactor CReP (Constitutive Repressor of eIF2α Phosphorylation; also known as PPP1R15B). These findings demonstrate that the modulation of eIF2α-specific phosphatase cofactor activity can be a rheostat of cellular homeostasis that initiates a functional ISR and suggest that the HIV-PIs could be repositioned as therapeutics in human diseases to modulate translation rates and stress responses.

Keywords: ER stress; HIV protease inhibitors; Nelfinavir; PPP1R15B; translation initiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism
  • Animals
  • Eukaryotic Initiation Factor-2 / metabolism*
  • HIV Protease / metabolism*
  • HIV Protease Inhibitors / pharmacology*
  • HeLa Cells
  • Humans
  • Liver / drug effects
  • Liver / metabolism
  • Membrane Proteins / deficiency
  • Membrane Proteins / metabolism
  • Mice
  • Nelfinavir / pharmacology
  • Phosphorylation / drug effects
  • Protein Phosphatase 1 / metabolism
  • Protein Serine-Threonine Kinases / deficiency
  • Protein Serine-Threonine Kinases / metabolism
  • RNA, Small Interfering / metabolism
  • Stress, Physiological / drug effects*
  • Transcription, Genetic / drug effects
  • Unfolded Protein Response / drug effects
  • eIF-2 Kinase / metabolism


  • Eukaryotic Initiation Factor-2
  • HIV Protease Inhibitors
  • Membrane Proteins
  • RNA, Small Interfering
  • Activating Transcription Factor 4
  • Ern2 protein, mouse
  • Protein Serine-Threonine Kinases
  • eIF-2 Kinase
  • Protein Phosphatase 1
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1
  • Nelfinavir