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Multiple levels of PKR inhibition during HIV‐1 replication
Author(s) -
Clerzius Guerline,
Gélinas JeanFrançois,
Gatignol Anne
Publication year - 2011
Publication title -
reviews in medical virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.06
H-Index - 90
eISSN - 1099-1654
pISSN - 1052-9276
DOI - 10.1002/rmv.674
Subject(s) - protein kinase r , eif 2 kinase , biology , activator (genetics) , interferon , rna , viral replication , protein kinase a , virology , kinase , virus , microbiology and biotechnology , mitogen activated protein kinase kinase , gene , biochemistry , cyclin dependent kinase 2
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. Copyright © 2010 John Wiley & Sons, Ltd.