CXC Chemokines and HIV Pathogenesis

描述(申请人提供)：我们最近发现，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：白介素8(IL-8)和生长调节癌基因α(Gro-α)。这种刺激似乎是通过一条涉及酪氨酸激酶、PKC-Zeta、可能还有核因子-kappaB的途径来实现的。然后，IL-8和Gro-α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它们的受体CXCR1和/或CXCR2，我们可以抑制HTV-1的复制。公司已经开发了阻断上述趋化因子功能的药物来治疗炎症性疾病，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的HIV临床分离株刺激Gro-α和EL-8产生的程度。还将评估IL-8和Gro-α对一系列艾滋病毒分离株复制的影响。这些实验将阐明这些涉及趋化因子、受体和HIV的自分泌/旁分泌环路的广泛适用性，因此在临床上具有重要意义。我们将进一步测试这一假设，即艾滋病毒刺激PKC-Zeta，从而刺激NF-kappaB，导致IL-8和Gro-α的转录和生产增加，这反过来通过增加病毒进入刺激艾滋病毒的复制。因此，拟议的 研究旨在进一步验证Gro-α和EL-8及其受体作为抗逆转录病毒治疗的靶点。从机制上理解艾滋病毒和这些C-X-C趋化因子之间的相互作用可能会导致开发治疗艾滋病毒感染患者的新方法。

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.