tRNA A58-methyltransferase as a Target for HIV Therapy

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DESCRIPTION (provided by applicant): During the first stage of HIV nucleic acid replication, HIV reverse transcriptase catalyzes the extension of host tRNA3lys after the annealing of its 3'-18 nucleotides to a complementary 18-nt viral site, In the late stages of replication, this 18-nt site is recapitulated without replication of the entire tRNA. Evidence suggests that a post-transcriptional modification (N-1 methyl A58 ) found in the 19th nucleotide from the 3'-end of the priming tRNA limits replication to 18 nucleotides. If HIV replication is primed with unmodified tRNA3lys in purified biochemical systems, replication aborts after the tRNA copying step accompanying the second strand transfer reaction. We propose to test the hypothesis that tRNA A58 -methyltransferase is an essential enzyme required for successful HIV infection, and that it can be inhibited without toxic consequences for the host within a therapeutic window. We plan to determine whether diminished levels of tRNA A58- methyltransferase in cultured cells produce non-infectious HIV particles and whether human cells with diminished levels of tRNA A58-methyltransferase retain viability. If these conditions are met, tRNA A58- methyltransferase should provide a host target for anti-HIV intervention.