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S3 Reverse Transcriptase-Associated Ribonuclease H Activity as a Therapeutic Target. S. F. J. LE GRICE*. NCI-FCRDC, Frederick, MD.
p66/p51 HIV reverse transcriptase (RT) possesses a ribonuclease H (RNase H) domain at the C-terminus of its p66 subunit, the role of which is hydrolysis of RNA in the RNA/DNA replication intermediate. Preliminary studies in our laboratory have demonstrated that elimination RNase H function through site-directed mutagenesis impairs virus replication, indicating this retroviral function cannot be complemented by a cellular counterpart and rendering it a bona fide target for therapeutic intervention. However, while considerable effort has been devoted to developing nucleoside-and nonnucleoside-based inhibitors of retroviral DNA polymerase function, there have been only a few reports potent and selective RNase H inhibitors. The goal of this presentation is to review RNase H function with regard to highly specific events in HIV replication requiring a high degree of specificity from this domain. The current status of RNase H inhibitors will also be reviewed.
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