CXC Chemokines and HIV Pathogenesis

描述（由申请人提供）：我们最近的研究表明，当单核细胞来源的巨噬细胞（MDM）暴露于HIV-1时，它们会产生大量的两种C-X-C趋化因子：白细胞介素8 （IL-8）和生长调节癌基因α (gro - α)。这种刺激似乎是由涉及酪氨酸激酶、PKC-zeta和NF-kappaB的途径介导的。然后，IL-8和GRO-alpha反过来反馈并刺激MDM和淋巴细胞中的HIV-1复制，可能是通过增加病毒进入。通过阻断这些趋化因子或其受体cxcr1和/或CXCR2，我们可以抑制HTV-1的复制。公司已经开发出阻断上述趋化因子功能的药物，以治疗炎症性疾病，我们已经证明了CXCR2的小分子抑制剂能够抑制HIV-1的复制。我们现在建议检查不同临床分离的HIV刺激gro - α和EL-8产生的程度。还将评估IL-8和gro - α对一系列HIV分离株复制的影响。这些实验将阐明这些涉及趋化因子、受体和HIV的自分泌/旁分泌循环的广泛适用性，从而阐明其临床重要性。我们将进一步验证HIV刺激PKC-zeta和NF-kappaB的假设，从而导致IL-8和gro - α的转录和产生增加，从而通过增加病毒进入刺激HIV复制。因此，提议的

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.