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GCN2 has inhibitory effect on human immunodeficiency virus-1 protein synthesis and is cleaved upon viral infection

Javier del Pino1, José Luis Jiménez, Iván Ventoso

  • 1Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, Madrid, Spain.

Plos One
|October 31, 2012
PubMed

Insights

Human immunodeficiency virus (HIV-1) infection triggers the cleavage of GCN2, an enzyme that normally inhibits viral protein synthesis. HIV-1 protease inactivates GCN2, promoting viral replication.

Area of Science:

  • Molecular Biology
  • Virology
  • Cellular Stress Response

Background:

  • Eukaryotic translation initiation factor 2 alpha (eIF2alpha) phosphorylation is a key stress response controlling protein synthesis.
  • GCN2 kinase plays a role in antiviral defense against certain RNA viruses and HIV-1.
  • HIV-1 has evolved mechanisms to counteract PKR, another eIF2alpha kinase involved in antiviral responses.

Purpose of the Study:

  • To investigate the role of GCN2 in HIV-1 infection.
  • To determine if HIV-1 proteases interact with and affect GCN2 function.
  • To elucidate the mechanism by which HIV-1 evades GCN2-mediated translational control.

Main Methods:

  • Infection of human cells with HIV-1 and HIV-2.
  • In vitro proteolysis assays using purified HIV-1 and HIV-2 proteases with GCN2.
  • Transfection of cell lines with HIV-1 cDNA clones.
  • Analysis of GCN2 activation, eIF2alpha phosphorylation, and viral protein synthesis.
  • Use of GCN2 knockout cells and cells with varying levels of phosphorylated eIF2alpha.

Main Results:

  • HIV-1 infection leads to the proteolytic cleavage of GCN2 in human cells.
  • Purified HIV-1 and HIV-2 proteases directly cleave GCN2 in vitro, inhibiting its activation by viral RNA.
  • HIV-1 replication activates GCN2 and eIF2alpha phosphorylation.
  • GCN2 knockout or low eIF2alpha phosphorylation conditions enhance HIV-1 protein synthesis.
  • Overexpression of GCN2 reduces viral protein synthesis.

Conclusions:

  • Viral RNA during HIV-1 infection activates GCN2, inhibiting viral translation.
  • HIV-1 protease cleaves GCN2 to counteract this antiviral effect and promote viral replication.
  • GCN2 represents a potential target for antiviral strategies against HIV-1.

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