CXC Chemokines and HIV Pathogenesis

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DESCRIPTION (provided by applicant): We have recently shown that when monocyte-derived macrophages (MDM) are exposed to HIV-1, they produce large amounts of two C-X-C chemokines: Interleukin 8 (IL-8) and Growth-Regulated Oncogene alpha (GRO-alpha). This stimulation appears to be mediated by a pathway involving a tyrosine kinase, PKC-zeta, and perhaps NF-kappaB. IL-8 and GRO-alpha then, in turn, feed back and stimulate HIV-1 replication in both MDM and lymphocytes, likely by increasing viral entry. By blocking these chemokines or their receptors, CXCR1and/or CXCR2, we can inhibit HTV-1 replication. Companies have already developed agents that block the function of the above chemokines in order to treat inflammatory diseases, and we have demonstrated that a small molecule inhibitor of CXCR2 is able to inhibit HIV-1 replication. We now propose to examine the magnitude to which diverse clinical isolates of HIV stimulate the production of GRO-alpha and EL-8. The effect of IL-8 and GRO-alpha on the replication of a range of HIV isolates will also be assessed. These experiments will clarify how broadly applicable, and hence clinically important, these autocrine/paracrine loops involving chemokine, receptor, and HIV are. We will further test the hypothesis that HIV stimulates PKC-zeta and hence NF-kappaB, leading to increased transcription and production of IL-8 and GRO-alpha, which in turn stimulate HIV replication by augmenting viral entry. Thus, the proposed studies aim to further validate GRO-alpha and EL-8 and their receptors as targets for antiretroviral therapy. A mechanistic understanding of the interactions between HIV and these C-X-C chemokines could lead to the development of new approaches to the treatment of patients infected with HIV.