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）的复制受与人细胞蛋白相互作用的调节。影响病毒复制和发病机制的细胞因子是细胞因子。趋化因子是细胞因子的一个亚家族，其受体在HIV发病机制中起重要作用。我们的研究小组最近发现，在单核细胞衍生的巨噬细胞（MDM）暴露于HIV后，两种CXC趋化因子，白细胞介素-8（IL-8）和生长调节癌基因-α（GRO-α）的产生受到显著刺激，这与我们观察到的HIV感染患者外周血中IL-8表达与病毒载量相关一致。我们已经进一步证明，GRO-α和IL-8的产生是由病毒包膜蛋白gpl 20和CXCR 4受体的相互作用刺激的。IL-8和GRO-α然后反馈并刺激HIV-1在MDM和淋巴细胞中的复制，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CXCR 1和CXCR 2的作用，HIV-1复制被抑制。由于已经开发了阻断IL-8和GRO-α功能的药物来治疗炎性疾病，因此似乎这种自分泌/旁分泌环是HIV治疗的潜在靶标。 我们现在建议检查临床状态和HIV分离株诱导IL-8和GRO-α产生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IL-8和GRO-α产生增加与更晚期疾病相关的假设。我们还将定义HIV诱导这两种趋化因子产生的分子水平事件，检验CXCR 4的gp 120参与刺激PKC和NF-κ B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-α增强HIV复制的机制，假设这些趋化因子增加病毒进入。对IL-8、GRO-α及其受体之间分子相互作用的机制理解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.