3rd Conference on Retroviruses and Opportunistic Infections Washington, DC - January 28-February 1, 1996

Conf Retroviruses Opportunistic Infect 1996 Jan 28-Feb 1; 3rd:53 (abstract no. 5)

Gao WY, Ahluwalia GS, Johns DG, Mitsuya H
National Cancer Institute, NIH, Bethesda, MD.

The selective advantage given by anti-HIV-l drug treatment to the replication of drug-resistant mutants is a major cause of the failure of HIV monotherapy. Since HIV-1 drug-resistance is a consequence of the rapid rate of virus turnover and a resulting high mutation frequency, a non-discriminative suppression of both wild-type and mutant proviral DNA replication is essential for permanent termination of HIV-1 infection. We find that limiting the DNA precursor nucleotide dTTP by low concentrations of thymidylate synthase inhibitors (FUdR and 5FU) non-discriminately inhibits HIV-1 at the prereplicational level when combined with AZT or D4T. In the presence of 0.2 micromolar FUdR, the 50% inhibitory concentrations of AZT or D4T were reduced by 6 and 8-fold, respectively. This reduction was a consequence of a reversible depletion of dTTP plus an enhanced 5'-phosphorylation of AZT and D4T by acompensatory increase in the AZT and D4T-phosphorylating enzyme thymidine kinase, which is under feedback regulatory control by dTTP. The combination of thymidylate synthase inhibitors with AZT or D4T thus offers a non-discriminative strategy to inhibit HIV-1 at both the prereplicational and replicational levels.

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