The interferon-induced protein kinase RNA activated (PKR) is activated after virus infection. This activation is transient during the human immunodeficiency virus type 1 (HIV-1) infection of lymphocytes, and the protein is not activated at the peak of infection. We observed that interferon-induced adenosine deaminase acting on RNA 1-p150 (ADAR1-p150) and ADAR1-p110 expression increases while the virus replicates actively. Furthermore, both forms of ADAR1 show enhanced interactions with PKR at the peak of HIV infection, suggesting a role for this protein in the regulation of PKR activation. We observed that ADAR1-p150, as previously shown for the TAR RNA binding protein (TRBP), reverses the PKR inhibition of HIV expression and production in HEK 293T cells. This activity requires the Z-DNA binding motif and the three double-stranded RNA binding domains but not the catalytic domain. In astrocytic cells, ADAR1-p150 increased HIV expression and production to an extent similar to that of TRBP. Small interfering RNAs against ADAR1-p150 moderately decreased HIV production. These results indicate that two interferoninduced proteins, ADAR1 and PKR, have antagonistic functions on HIV production. They suggest that ADAR1 and TRBP belong to a multiprotein complex that inhibits PKR during the HIV infection of lymphocytes.

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The adenosine deaminases acting on RNA (ADARs) are double-stranded RNA (dsRNA) binding enzymes that catalyze RNA editing of cellular and viral dsRNAs by deamination, which converts adenosines into inosines (6,22,54). Inosine is recognized as a guanosine, and thereby deamination alters the sequence-or structure-specific recognition of RNAs, their translation, and, consequently, the amino acid sequences of several proteins. This process also affects noncoding RNA, and the modification of microRNA (miRNA) sequences is very important in the RNA interference (RNAi) pathway that regulates posttranscriptional gene expression (35,53,54). In vertebrate cells, there are three genes that code for the ADAR1, ADAR2, and ADAR3 proteins. The mammalian Adar1 gene encodes two forms of the ADAR1 protein: the interferon (IFN)-inducible ϳ150-kDa form (p150) found in both the cytoplasm and the nucleus and the constitutively expressed ϳ110-kDa form (p110) found only in the nucleus (40, 90). These two forms are generated through alternative promoters (one of which is IFN inducible) and alternative splicing of exon