CXC Chemokines and HIV Pathogenesis

CXC 趋化因子和 HIV 发病机制

• 批准号: 6946547
• 负责人: David Michael Markovitz
• 金额: $ 18.17万
• 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/6946547
• 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，当单核细胞衍生的巨噬细胞（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）和生长调节的癌型癌α（GRO-Alpha（GRO-Alpha））。这种刺激似乎是由涉及酪氨酸激酶，PKC-Zeta甚至NF-kappab的途径介导的。然后，IL-8和GRO-α然后又可能通过增加病毒进入的MDM和淋巴细胞刺激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。公司已经开发了阻断上述趋化因子功能以治疗炎症性疾病的功能的药物，我们已经证明，CXCR2的小分子抑制剂能够抑制HIV-1的复制。现在，我们建议研究HIV的多种临床分离株刺激GRO-ALPHA和EL-8的产生。还将评估IL-8和Gro-α对复制HIV分离株的复制的影响。这些实验将阐明这些涉及趋化因子，受体和HIV的自分泌/旁分泌环的广泛适用，因此在临床上很重要。我们将进一步检验以下假设：HIV刺激PKC-Zeta及其NF-Kappab，从而导致IL-8和GRO-ALPHA的转录和产生增加，这反过来又通过增强病毒进入而刺激HIV复制。因此，提议 研究旨在进一步验证GRO-ALPHA和EL-8及其受体作为抗逆转录病毒疗法的靶标。对HIV与这些C-X-C趋化因子之间相互作用的机械理解可能会导致开发新方法来治疗感染HIV的患者。