Multiple Levels of PKR Inhibition During HIV-1 Replication

Rev Med Virol. 2011 Jan;21(1):42-53. doi: 10.1002/rmv.674. Epub 2010 Dec 7.

Abstract

Recent therapeutic approaches against HIV-1 include IFN in combination therapy for patients with coinfections or as an alternative strategy against the virus. These treatment options require a better understanding of the weak efficacy of the IFN-stimulated genes, such as the protein kinase RNA-activated (PKR), which results in viral progression. Activated PKR has a strong antiviral activity on HIV-1 expression and production in cell culture. However, PKR is not activated upon HIV-1 infection when the virus reaches high levels of replication, due to viral and cellular controls. PKR is activated by low levels of the HIV-1 trans-activation response (TAR) RNA element, but is inhibited by high levels of this double-stranded RNA. The viral Tat protein also counteracts PKR activation by several mechanisms. In addition, HIV-1 replicates only in cells that have a high level of the TAR RNA binding protein (TRBP), a strong inhibitor of PKR activation. Furthermore, increased levels of adenosine deaminase acting on RNA (ADAR1) are observed when HIV-1 replicates at high levels and the protein binds to PKR and inhibits its activation. Finally, the PKR activator (PACT) also binds to PKR during HIV-1 replication with no subsequent kinase activation. The combination of all the inhibiting pathways that prevent PKR phosphorylation contributes to a high HIV-1 production in permissive cells. Enhancing PKR activation by counteracting its inhibitory partners could establish an increased innate immune antiviral pathway against HIV-1 and could enhance the efficacy of the IFN treatment.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Down-Regulation*
  • HIV Infections / drug therapy
  • HIV Infections / enzymology*
  • HIV Infections / genetics
  • HIV Infections / virology
  • HIV-1 / drug effects
  • HIV-1 / genetics
  • HIV-1 / physiology*
  • Humans
  • Protein Kinase Inhibitors / pharmacology
  • Virus Replication* / drug effects
  • eIF-2 Kinase / antagonists & inhibitors*
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism

Substances

  • Protein Kinase Inhibitors
  • eIF-2 Kinase