As part of a larger effort to understand unique aspects of AIDS pathogenesis that might be exploited in novel therapeutic approaches, the principal investigator will focus on the critical role of HIV-infected monocytes and macrophages in certain aspects of HIV disease. He can now show that infection with HIV-1 results in abnormal priming of monocytes, leading to an atypical activation phenotype upon subsequent stimulation with cytokines or bacterial endotoxin. This HIV infection-mediated priming is highly aberrant in the sense that HIV-primed cells produce certain factors (e.g., nitric oxide) that are not made at all by uninfected cells, as well as release of other biologic mediators (e.g., TNFa, IL-6) in significantly higher amounts than their uninfected counterparts. This pattern suggests a """"""""hyperactivated"""""""" phenotype for HIV-infected monocytes that may contribute in unforeseen ways to the immune dysregulation in AIDS. Of particular importance, their pilot work shows that HIV-infected monocytes, in the absence of any additional stimulation, produce a specific set of chemotactic and activating cytokines (chemokines) known as macrophage inflammatory proteins (MIPs). Since MIPs, together with another chemokine RANTES, have been shown to constitute an elusive factor that controls HIV-1 replication during the early stages of the disease, the need for the analysis of mechanisms of their regulation during HIV-1 infection becomes imperative. As an approach to developing therapeutic strategies against this abnormal hyperactivation of monocytes by HIV-1, the principal investigator proposes, base on his preliminary results that show a marked dependence of HIV-infected monocytes on NO production for establishment of the activated phenotype, to investigate the effect of several in-house candidate drugs. These novel argininomimetic compounds act indirectly to inhibit NO synthase activity and NO production in human monocytes, and, therefore, might be useful in reducing the pathological effects of HIV-1 infection. Taken together, these aims should provide significant new insights into the mechanisms by which HIV-1 induces certain disease manifestations, thus helping to define novel targets for therapeutic intervention aimed at normalizing immune function of monocytes in HIV disease and AIDS.
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