CYTOKINE DYSFUNCTION AND LUNG 5LO METABOLISM IN AIDS

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Infection with the HIV leads to the development of AIDS. The alveolar macrophage (AM), which is the main resident inflammatory cell and defender of the lung against foreign microbes, can be affected by HIV disease. AM function is altered in HIV disease through direct infection with HIV, but also by the altered environmental milieu in AIDS. Although not infected by HIV, PMN dysfunction also occurs in AIDS. One group of Thl cytokines, granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin (IL)-3, interferon (IFN)gamma, as well as G-CSF have decreased levels in AIDS. Furthermore, there is an increase in the Th2 cytokines levels. The objective of this proposal is to examine the role of cytokine dysfunction in the regulation of AM, PBM and PMN dysfunction. Preliminary data suggests that synthesis of LT, which are 5-lipoxygenase (5-LO) metabolites of arachidonic acid, are reduced in AM, PBM, and PMN from HIV-infected subjects. We have evidence that cytokine dysfunction in HIV disease results in decreased 5-LO product synthetic capacity and is associated with reduced cellular killing of M. avium and BCG. Augmentation of LT levels in AM, PBM, and PMN following therapy with GM-CSF and G-CSF increases antimicrobial activity against M.avium and BCG. The hypothesis is that reduced colony stimulating factor levels, along with increased IL-4 levels suppress LT synthesis in AM, PBM, and PMN from HIV-infected subjects. This dysfunction in turn reduces phagocytic antimycobacterial activity. The specific aims are (1) to determine the mechanisms by which CD4 T cell dysfunction reduce AM, PBM, and PMN 5-LO metabolism in AIDS. In addition, (2) we will investigate the mechanisms by which G-CSF expression in AM and PBM is regulated in HIV disease, and its impact on PMN 5-LO metabolism. Furthermore, (3) we will examine the role of LT in the increased antimycobacterial activity of AM, PBM, and PMN following GM-CSF and G-CSF therapy. The experimental approach will be to examine the role of depletion of CD4 T cells and Thl/Th2 cytokine dysfunction on 5-LO metabolism in AM, PBM, and PMN. We will characterize the regulation of G-CSF expression in macrophages in AIDS. Finally, we will examine the role LT play in the increased antimycobacterial activity of AM, PBM, and PMN following CSF therapy. In summary, we will characterize a crucial defect in cytokine and subsequent 5-LO metabolism in AM, PBM, and PMN which occurs in AIDS. This proposal will further enhance our ability to correct this defect and help boost AM, PBM, and PMN defenses against opportunistic infections in the lung in HIV disease.