CXC Chemokines and HIV Pathogenesis

描述(由申请人提供)：人类免疫缺陷病毒1型(HIV-1)的复制受与人类细胞蛋白相互作用的调节。在影响病毒复制和致病的细胞因素中，细胞因子就是其中之一。趋化因子是细胞因子的一个亚家族，其受体在HIV的发病机制中起重要作用。我们的团队最近发现，单核细胞来源的巨噬细胞(MDM)暴露于HIV后，两种CXC趋化因子--白介素8(IL-8)和生长调节癌基因-α(Gro-α)的产生明显受到刺激，这与我们的观察结果一致，即HIV感染患者淋巴管中IL-8的表达与病毒载量有关。我们进一步证明，Gro-α和IL-8的产生受到病毒包膜蛋白gpl20和CXCR4受体相互作用的刺激。IL-8和Gro-α随后反馈并刺激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CXCR2的作用，HIV-1的复制被抑制。随着阻断IL-8和Gro-α功能的药物已被开发用于治疗炎症性疾病，这种自分泌/旁分泌环路似乎是HIV治疗的潜在靶点。 我们现在建议检查临床状态和HIV分离株诱导产生IL-8和Gro-α的能力之间的相关性。我们还将评估临床状态与HIV分离株对IL-8和Gro-α的反应之间的相关性。这些研究将检验这一假设，即IL-8和Gro-α的产生增加与更严重的疾病有关。我们还将定义HIV诱导这两种趋化因子产生的分子水平的事件，验证GP120与CXCR4的结合刺激PKC和NF-kB活性，从而导致IL-8和Gro-α转录和表达增加的假设。我们还将详细介绍IL-8和Gro-x在这些趋化因子增加病毒进入的假设下增强艾滋病毒复制的机制(S)。从机制上理解IL-8、Gro-α和它们的受体之间的分子相互作用可能会导致开发治疗HIV感染患者的新方法。

DESCRIPTION (provided by applicant): Replication of the Human Immunodeficiency Virus type 1 (HIV-1) is regulated by interactions with human cellular proteins. Among the cellular factors that influence both viral replication and pathogenesis are the cytokines. Chemokines, a subfamily of the cytokines, and their receptors have been shown to be important in HIV pathogenesis. Our group recently found that production of two CXC chemokines, Interleukin-8 (IL-8) and Growth-Regulated Oncogene-alpha (GRO-alpha), is markedly stimulated following exposure of monocyte-derived macrophages (MDM) to HIV, consistent with our observation that IL-8 expression in the lymphatics of HIV-infected patients correlates with viral load. We have further demonstrated that GRO-alpha and IL-8 production is stimulated by the interaction of the viral envelope protein gpl20 and the CXCR4 receptor. IL-8 and GRO-alpha then feed back and stimulate HIV-1 replication in both MDM and lymphocytes, likely by increasing viral entry. By blocking the action of these chemokines or their receptors, CXCR1 and CXCR2, HIV-1 replication is inhibited. As agents that block the function of IL-8 and GRO-alpha have been developed to treat inflammatory diseases, it would appear that this autocrine/paracrine loop is a potential target for HIV therapeutics. We now propose to examine the correlation between clinical status and the ability of HIV isolates to induce production of IL-8 and GRO-alpha. We will also assess the correlation between clinical status and the response of HIV isolates to IL-8 and GRO-alpha. These studies will test the hypothesis that increased production of IL-8 and GRO-alpha is associated with more advanced disease. We will also define the molecular-level events by which HIV induces the production of these two chemokines, testing the hypothesis that gp 120 engagement of CXCR4 stimulates the activity of PKC and NF-kB, which leads to increased transcription and expression of IL-8 and GRO-alpha. We will also detail the mechanism(s) by which IL-8 and GRO-(x augment HIV replication, working under the hypothesis that these chemokines increase viral entry. A mechanistic understanding of the molecular interplay between IL-8, GRO-alpha, and their receptors could lead to the development of new approaches to the treatment of HIV-infected patients.