. The long-term goal of this proposal is to gain a better understanding of the role of macrophages in the pathogenesis of AIDS. The rationale for this proposal is based on the evidence of widespread infection of tissue macrophages with HIV, high levels of monokines (IL-1, IL-6, TNFa, 7kDa T cell inhibitory monokine, TCIM) production in individuals with symptomatic HIV infection, and sustained production of certain monokines (IL-1a, IL-6, 7kDa TCIM) following in vitro HIV-1 infection of normal macrophages or macrophage tumor cells in investigator's model system. It is hypothesized that the sustained production of these monokines with immunoregulatory and inflammatory activities mediates the major disease manifestations of HIV infection.
The specific aims are: 1. To elucidate the mechanism of sustained IL-1a release by HIV-1 infected macrophages. Transcriptional regulation will be studied utilizing IL-1a gene promoter/reporter gene (CAT) constructs transfected into macrophages and T cells infected with HIV or co-transfected with HIV gene constructs. Post-transcriptional regulation and production and release of IL-1a will be studied in long-term macrophage cultures. 2. To obtain cDNA clones of the novel 7kDa T cell inhibitory monokine (TCIM) produced by HIV-1 infected macrophages for future studies on the regulation and pathogenic role of this monokine in AIDS, by screening with a neutralizing monoclonal antibody obtained in previous studies. 3. To define the viral requirements and role of monokines (IL-1a, Il-6, 7kDa TCIM) In a novel system of in vitro tumorigenesis dependent on HIV-1 infected macrophages.
