CXC Chemokines and HIV Pathogenesis

CXC 趋化因子和 HIV 发病机制

• 批准号: 7050061
• 负责人: David Michael Markovitz
• 金额: $ 37.35万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-15 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7050061
• 关键词: chemokine; chemokine receptor; clinical research; human immunodeficiency virus 1; human subject; interleukin 8; macrophage; molecular pathology; nuclear factor kappa beta; pathologic process; protein kinase C; tissue /cell culture; virus infection mechanism; virus replication

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.

描述（由申请人提供）：我们最近表明，当单核细胞源性巨噬细胞 (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 以及可能还有 NF-kappaB 的通路介导的。然后，IL-8 和 GRO-α 可能通过增加病毒进入而反过来反馈并刺激 MDM 和淋巴细胞中的 HIV-1 复制。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 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，并且我们已经证明CXCR2的小分子抑制剂能够抑制HIV-1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 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/旁分泌环路的适用范围有多么广泛，因此在临床上也很重要。我们将进一步检验这样的假设：HIV 刺激 PKC-zeta，从而刺激 NF-kappaB，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来刺激 HIV 复制。因此，建议的 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。对 HIV 与这些 C-X-C 趋化因子之间相互作用的机制了解可能会导致开发治疗 HIV 感染患者的新方法。