The project continued to focus on developing a rapid and sensitive assay to measure the cell-associated viral burden in peripheral blood leukocytes (PBL) from HIV-1/-2 infected individuals. In individuals, it focused on the anti-retroviral activity of a novel drug, 9-nitrocamptothecin (9NC), (9NC), a semi-synthetic/water-insoluble compound derived from the plant alkaloid camptothecin (CPT). 9NC is currently in phase II clinical trials in cancer patients, and recent pre-clinical studies have demonstrated that 9NC inhibits the induction of HIV-1 replication up to approximately 95% in a TNF-alpha-induced human T cell line clone in culture. 9NC blocks both infected and un-infected lymphocytic cells at the boundary of S/G2-phases of cell cycle. Moreover,, the observed inhibition by 9NC correlates with enhanced apoptosis in infected, but not un-infected cells. The primary target of 9NC is the nuclear enzyme topoisomerase I (topo I), but other cellular and/or viral factors may also participate in the anti-HIV activity of 9NC. The compound also stimulates the transcription factor NF- kappaB, eliciting NF-kappaB1(P50)/rel A(p65) heterodimer formation which is independent of cellular transcription or translation, suggesting that topo I is unlikely to be involved in NF-kappaB activation). Furthermore, 9NC could have dual therapeutic advantages, both in the suppression of HIV replication and eradication of cancer cells in AIDS-associated malignancies such as Kaposi's sarcoma, Hodgkin's and non-Hodgkins lymphoma.
