In this phase II SBIR application the investigators wish to evaluate in vitro and in vivo two relatively new ribonucleotide reductase inhibitors, Didox and Trimidox, for their ability to inhibit HIV replication and to enhance the activity of currently used anti-HIV agents. A considerable amount of work has been done by numerous groups to evaluate hydroxyurea as an anti-HIV agent, and some promising results have been found. In vitro studies have indicated that HU can inhibit HIV replication and can potentiate many of the anti-HIV nucleoside analogs due to its inhibition of ribonucleotide reductase. A number of clinical trials have been undertaken to evaluate the activity of HU on HIV infection and its effects on ddI activity. The results of these trials have been mixed. HU does not appear effective against HIV when administered alone, and it has been shown to potentiate the activity of ddI in some studies but not others. The investigators of this proposal argue that their agents should be better than HU due to higher potency and lower toxicity. Specifically, they plan to: 1) determine the effect of their compounds on HIV replication in vitro, 2) determine the ability of their compounds to potentiate the activity of anti-HIV nucleoside analogs and protease inhibitors, 3) determine the effect of their compounds on drug resistant strains of HIV, 4) determine the best treatment protocols, 5) evaluate acute and chronic toxicity of their agents alone and in combination with anti-HIV agents, and 6) study the pharmacology of their agents.
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