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These treatment options require a better understanding of the weak efficacy of the IFN\u2010stimulated genes, such as the protein kinase RNA\u2010activated (PKR), which results in viral progression. Activated PKR has a strong antiviral activity on HIV\u20101 expression and production in cell culture. However, PKR is not activated upon HIV\u20101 infection when the virus reaches high levels of replication, due to viral and cellular controls. PKR is activated by low levels of the HIV\u20101 <jats:italic>trans<\/jats:italic>\u2010activation response (TAR) RNA element, but is inhibited by high levels of this double\u2010stranded RNA. The viral Tat protein also counteracts PKR activation by several mechanisms. In addition, HIV\u20101 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\u20101 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\u20101 replication with no subsequent kinase activation. The combination of all the inhibiting pathways that prevent PKR phosphorylation contributes to a high HIV\u20101 production in permissive cells. Enhancing PKR activation by counteracting its inhibitory partners could establish an increased innate immune antiviral pathway against HIV\u20101 and could enhance the efficacy of the IFN treatment. 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