ADAR1 and PKR, interferon stimulated genes with clashing effects on HIV-1 replication

The induction of hundreds of Interferon Stimulated Genes (ISGs) subsequent to virus infection generates an antiviral state that functions to restrict virus growth at multiple steps of their replication cycles. In the context of Human Immunodeficiency Virus-1 (HIV-1), ISGs also possess antiviral functions, but some ISGs show proapoptotic or proviral activity. One of the most studied ISGs, the RNA activated Protein Kinase (PKR), shuts down the viral protein synthesis upon activation. HIV-1 has evolved to evade its inhibition by PKR through viral and cellular mechanisms. One of the cellular mechanisms is the induction of another ISG, the Adenosine Deaminase acting on RNA 1 (ADAR1). ADAR1 promotes viral replication by acting as an RNA sensing inhibitor, by editing viral RNA and by inhibiting PKR. This review challenges the orthodox dogma of ISGs as antiviral proteins, by demonstrating that two ISGs have opposing and clashing effects on viral replication.