Pathogenesis of Hepatic Injury with HCV/HIV Coinfection

描述：(申请人提供)本提案的主要目标是 为了研究丙型肝炎病毒(丙型肝炎病毒)和人类免疫缺陷病毒 (HIV)包膜蛋白可能协同作用触发信号事件 导致肝细胞炎症和细胞凋亡。与艾滋病毒合并感染 丙型肝炎病毒预后很差，伴有进行性肝功能障碍 通常会导致肝硬变和死亡。静脉注射吸毒者和 血友病患者合并感染的发生率很高，并面临着这种严峻的后果。 为什么合并感染的宿主有如此高的进展性肝病发病率？这个 丙型肝炎病毒相关性肝炎的发病机制被认为部分是由于 免疫介导性炎症及其直接感染的影响 肝细胞。我们的初步数据表明了一种新的第三种潜在机制 肝脏炎症和细胞凋亡。我们在HepG2细胞和原代细胞中观察到 用丙型肝炎病毒包膜蛋白E2联合治疗的肝细胞 用HIV gp20诱导炎性趋化因子IL-8和 引发了细胞凋亡。这些功能结果发生在纳摩尔 E_2和GP_(120)浓度对应于同源物的Kd 与其各自的受体CDS1和CXCR4结合的配体，并 与特定信号分子的激活有关，包括Src 家族Lyn激酶、RAFTK/Pyk2、Erk1/2和p38 MAP激酶，以及Fas配体。 这些数据表明，促炎和凋亡事件可能是由于 通过“无辜的旁观者”双重接触丙型肝炎病毒和艾滋病病毒的包膜蛋白 机制。这项提议试图描述IL-8的分子机制 丙型肝炎病毒E2和人类免疫缺陷病毒gp20诱导细胞凋亡的程序。一个 提出了一种有重点的实验方法来描述信号事件 起源于特定的细胞表面受体，通过 中间信号分子，并聚集在转录激活子上 MAP激酶家族。阐明这些丙型肝炎病毒和艾滋病病毒包膜蛋白是如何 与肝细胞的相互作用不仅可以加深我们对 疾病的发病机制在重叠感染的宿主中也会导致靶向 改善此类患者目前不良预后的治疗策略 个人。

DESCRIPTION: (provided by applicant) The primary objective of this proposal is to examine how the hepatitis C virus (HCV) and the human immunodeficiency virus (HIV) envelope proteins may act collaboratively to trigger signaling events that contribute to hepatocyte inflammation and apoptosis. Coinfection with HIV and HCV confers a poor prognosis, with progressive hepatic dysfunction that often results in cirrhosis and death. Both intravenous drug users and hemophiliacs have a high incidence of coinfection and face this grim outcome. Why do coinfected hosts have such high rates of progressive liver disease? The pathogenesis of HCV-related hepatitis is believed to be due, in part, to immune-mediated inflammation as well as the effects of direct infection of hepatocytes. Our preliminary data suggest a novel third potential mechanism for hepatic inflammation and apoptosis. We observed in both HepG2 cells and primary hepatocytes that treatment with the HCV envelope protein E2, in conjunction with HIV gpl20, induced the inflammatory chemokine interleukin-8 (IL-8) and triggered apoptosis. These functional outcomes occurred at nanomolar concentrations of E2 and gp 120 that correspond to the Kd's for the cognate ligands binding to their respective receptors, CDS1 and CXCR4, and were associated with activation of specific signaling molecules, including the Src family Lyn kinase, RAFTK/Pyk2, Erkl/2 and p38 MAP kinases, and Fas-ligand. These data indicate that proinflammatory and apoptotic events may occur due to dual exposure to HCV and HIV envelope proteins via an "innocent bystander" mechanism. This proposal seeks to characterize the molecular mechanisms of IL-8 induction and the program of apoptosis caused by HCV E2 and HIV gpl20. A focused experimental approach is presented to delineate signaling events that originate at specific cell surface receptors, are transduced through intermediate signaling molecules, and converge on transcriptional activators of the MAP kinase family. Elucidating how these HCV and HIV envelope proteins may interact with hepatocytes could not only further our understanding of the pathogenesis of disease in coinfected hosts but also lead to targeted therapeutic strategies to improve the currently poor prognosis of such individuals.