. In this application the investigators propose to compare the inhibition of mitochondrial DNA synthesis by CBV with the inhibition by AZT and ddC. They will evaluate the inhibition of mitochondrial DNA replication in 3 model systems: intact cells, isolated mitochondria, and purified DNA polymerase gamma. If it is found that CBV is sufficiently different from the other agents with respect to its mechanism of toxicity, this information would argue for the development of CBV as an anti- HIV agent to replace or combine with current drugs. The investigator believes that knowledge obtained from such studies should aid in the design of rational drug combinations, which may diminish toxicities or could result in the design of treatment regimens to prevent the toxicity of these compounds without interfering with their anti-HIV activity. A second major objective of this work is to characterize the biochemical pharmacology and mechanism of action of a number of 6-substituted derivatives of CBV that are potent inhibitors of HIV replication. The investigator hopes that these studies would identify compounds with unique characteristics and aid in the decision to develop one or more of these agents as anti-HIV drugs.
