title: Multiple levels of PKR inhibition during HIV-1 replication.
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.
authors.affiliation: Lady Davis Institute for Medical Research, Montréal, QC, Canada.
authors.forename: Guerline
authors.initials: G
authors.lastname: Clerzius
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Gélinas
authors.forename: Anne
authors.initials: A
authors.lastname: Gatignol
mesh_terms: D000818:Animals; D015536:Down-Regulation; D015658:HIV Infections / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D019892:eIF-2 Kinase