Inhibition of the dsRNA-Dependent Protein Kinase by a Peptide Derived from the Human Immunodeficiency Virus Type 1 Tat Protein

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Abstract
The human immunodeficiency virus (HIV) is the etiologic agent leading to the development of acquired immunodeficiency syndrome (AIDS). Interferons (IFNs) are known for eliciting antiviral responses from cells, and studies have indicated that infection with HIV induces the production of IFN. Previous studies have shown that the trans-acting response element (TAR) sequence of HIV-1 mRNA can activate the IFN-induced double-stranded (ds) RNA-dependent protein kinase (DAI). DAI, when activated, is a potent inhibitor of protein synthesis and has been implicated in mediating part of IFN's antiviral activity. Here, we report that a synthetic peptide containing the basic region of HIV Tat protein is effective in preventing the activation of DAI. Evidence is presented that indicates that the Tat peptide exerts its effect by binding to the TAR RNA sequence and thus preventing this RNA from binding to and activating DAI. It appears that in addition to its role in trans-activation, the tat protein may also function to overcome the antiviral activity of IFN by regulating DAI activity. Thus, inhibition of DAI by the Tat protein early in the life cycle of HIV may provide a mechanism by which the virus can escape a translational block imposed by the kinase.