The overall objective of this proposal is to further purify the active component(s) of a pine cone extract which has immunopotentiating activity, and inhibits HIV replication in infected cells, and to develop it preclinically as a novel, efficacious, yet naturally occurring, therapeutic agent for AIDS Accumulated epidemiologic, clinical, virologic and immunologic data about HIV infection suggests that for an anti-HIV drug to be effective, it must inhibit HIV replication, have immune potentiating activity, and is not toxic or carcinogenic so that it can be administered lifelong. Recently, we have discovered that 2 partially purified extracts from cones of Japanese white pine (Pinus parviflora Sieb et Zucc) could inhibit HIV replication in CD4-positive human T cell lines. These extracts are relatively nontoxic and have differentiation and immune potentiating effects on blood cells, suggesting that they may be potentially useful therapeutic agents for the treatment of AIDS. This program proposes to: 1) Further purify the active component(s) of one of these extracts to homogeneity; 2) Determine the backbone structure of the active component; 3) Study its effects of HIV replication in human monocytic, T and B cells acutely infected with HIV; 4) Determine its mechanism of viral inhibition; 5) Study its impacts on cells chronically infected with HIV, and if it will correct the expression of cellular genes modulated by chronic HIV infection; 6) Determine whether viral inhibition is also mediated by its ability to induce lymphokine production, and if so, to purify the lymphokine(s) and to clone the gene encoding the lymphokine(s); and 7) Determine its in vivo toxicity and 8) metabolism in laboratory animals. This is a comprehensive program utilizing multidisciplinary expertise available in our laboratories, including tissue culture, virologic, molecular-biologic, pharmacologic, biochemical, chemical and immunologic techniques. Knowledge of the mechanism of HIV inhibition, identifying the affected HIV genes, determining the backbone structure of the active compound and analysizing its metabolism, toxicity and its ability to restore the expression of cellular proteins as evaluated in this project will assist in devising a novel therapeutic agent for controlling long-term HIV infection, treating patients with AIDS and restoring immune functions.
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