CXC Chemokines and HIV Pathogenesis

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DESCRIPTION (provided by applicant): Replication of the Human Immunodeficiency Virus type 1 (HIV-1) is regulated by interactions with human cellular proteins. Among the cellular factors that influence both viral replication and pathogenesis are the cytokines. Chemokines, a subfamily of the cytokines, and their receptors have been shown to be important in HIV pathogenesis. Our group recently found that production of two CXC chemokines, Interleukin-8 (IL-8) and Growth-Regulated Oncogene-alpha (GRO-alpha), is markedly stimulated following exposure of monocyte-derived macrophages (MDM) to HIV, consistent with our observation that IL-8 expression in the lymphatics of HIV-infected patients correlates with viral load. We have further demonstrated that GRO-alpha and IL-8 production is stimulated by the interaction of the viral envelope protein gpl20 and the CXCR4 receptor. IL-8 and GRO-alpha then feed back and stimulate HIV-1 replication in both MDM and lymphocytes, likely by increasing viral entry. By blocking the action of these chemokines or their receptors, CXCR1 and CXCR2, HIV-1 replication is inhibited. As agents that block the function of IL-8 and GRO-alpha have been developed to treat inflammatory diseases, it would appear that this autocrine/paracrine loop is a potential target for HIV therapeutics. We now propose to examine the correlation between clinical status and the ability of HIV isolates to induce production of IL-8 and GRO-alpha. We will also assess the correlation between clinical status and the response of HIV isolates to IL-8 and GRO-alpha. These studies will test the hypothesis that increased production of IL-8 and GRO-alpha is associated with more advanced disease. We will also define the molecular-level events by which HIV induces the production of these two chemokines, testing the hypothesis that gp 120 engagement of CXCR4 stimulates the activity of PKC and NF-kB, which leads to increased transcription and expression of IL-8 and GRO-alpha. We will also detail the mechanism(s) by which IL-8 and GRO-(x augment HIV replication, working under the hypothesis that these chemokines increase viral entry. A mechanistic understanding of the molecular interplay between IL-8, GRO-alpha, and their receptors could lead to the development of new approaches to the treatment of HIV-infected patients.