Acquired Immunodeficiency Syndrome (AIDS), a disease affecting millions of individuals worldwide, has a high incidence of patient mortality. The etiological agent of this disease, the infectious retrovirus HIV-l, has proven refractory to therapeutic intervention. The only drugs used in the clinic today target the viral reverse transcriptase. At best such drugs temporarily delay disease progression. In addition, these agents exhibit significant toxicity at the effective therapeutic dose. Presently, other compounds, targeting reverse transcriptase, viral protease, or the viral Tat trans-activator, ale also in clinical trials. However, it appears clear that additional drugs may be needed which target other steps in viral replication. One such target is the Rev trans-activator, which is essential for viral replication. The function of Rev is to induce-nuclear export of the partially spliced and unspliced viral messages, which encode the structural gene products and the RNA genome, for infectious HIV-1 particles. We propose to create a Rev-dependent, double reporter assay combined with Oncogene Science's unique cell based high-throughput screening technology, which is capable of evaluating over 123,000 compounds per year, to identify lead compounds from the NCI's natural product repository, which specifically inhibit the HIV-1 Rev trans- activator.
