RNase L inhibitor is induced during human immunodeficiency virus type 1 infection and down regulates the 2-5A/RNase L pathway in human T cells

The interferon-regulated 2-5A/RNASE L pathway plays a major role in the Antiviral and antiproliferative activities of these cytokines. Several viruses, however, have evolved strategies to escape the Antiviral activity of the 2-5A/RNASE L pathway. In this context, we have cloned a cDNA coding for the RNASE L Inhibitor (RLI), a protein that specifically inhibits RNASE L and whose regulated expression in picornavirus-infected cells down regulates the activity of the 2-5A/RNASE L pathway. We show here that RLI increases during the course of human immunodeficiency virus type 1 (HIV-1) Infection, which may be related to the downregulation of RNASE L activity that has been described to occur in HIV-infected cells. In order to establish a possible causal relationship between these observations, we have stably transfected H9 cells with RLI sense or antisense cDNA-expressing vectors. The overexpression of RLI causes a decrease in RNASE L activity and a twofold enhancement of HIV production. This increase in HIV replication correlates with an increase in HIV RNA and proteins. In contrast, reduction of RLI levels in RLI antisense cDNA-expressing clones reverses the inhibition of RNASE L activity associated with HIV multiplication and leads to a threefold decrease in the viral load. This anti-HIV activity correlated with a decrease in HIV RNA and proteins. These findings demonstrate that the level of RLI, via its modulation of RNASE L activity, can severely impair HIV replication and suggest the involvement of RLI in the inhibition of the 2-5A/RNASE L system observed during HIV Infection.