MECHANISM OF ACTION OF INTERFERON AGAINST HIV

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Interferons and dsRNA are anti-virals that have shown promise as agents in combatting infection with HIV. The work described in this research proposal will determine the mechanism by which interferon and dsRNA inhibit replication of HIV in acutely-infected cells. The proposed experiments will determine the site in replication of HIV in acutely-infected cells that is sensitive to treatment with interferon n. Experiments will be performed to determine if the interferoninduced pathways that have been implicated in inhibition of other viruses, the dsRNAdependent elF-2alpha protein kinase and the 2',5' oligo-adenylate synthetase/RNase L pathway, are activated in HIV-infected cells. Potential inhibitors of these pathways will be expressed in cell lines susceptible to infection with HIV to provide direct information concerning the importance of these pathways in inhibition of HIV replication. Since interferon and dsRNA are being tested in patients as a combination therapy with other anti-virals, the basic biological, biochemical, and molecular biological studies of the interactions between HIV and the interferon system proposed in this application may provide insights to allow better use of interferon, and agents that augment interferon's anti-viral activity in the clinic.