Pathogenesis of Hepatic Injury with HCV/HIV Coinfection

HCV/HIV 合并感染肝损伤的发病机制

• 批准号: 6657216
• 负责人: JEROME E GROOPMAN
• 金额: $ 8.5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6657216
• 关键词: CD95 molecule; HIV envelope protein gp120; HIV infections; apoptosis; comorbidity; hepatitis C; hepatitis C virus; human immunodeficiency virus 1; human tissue; inflammation; interleukin 8; liver cells; liver disorder; mitogen activated protein kinase; molecular pathology; protein protein interaction; transcription factor; virus envelope; virus protein; virus virus interaction

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.

描述：（由申请人提供）本提案的主要目标是 研究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， 导致肝细胞炎症和凋亡。合并感染艾滋病毒 和HCV预后差，伴有进行性肝功能障碍， 经常导致肝硬化和死亡。无论是静脉注射吸毒者， 血友病患者合并感染的发生率很高，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行性肝病发生率？的 HCV相关肝炎的发病机制被认为部分是由于 免疫介导的炎症以及直接感染 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HepG 2细胞和原代细胞中观察到， 用HCV包膜蛋白E2处理肝细胞， 与HIV gp 120一起，诱导炎性趋化因子白细胞介素-8（IL-8）， 引发了细胞凋亡这些功能性结局发生在纳摩尔 对应于同源物Kd的E2和gp 120浓度 配体结合其各自的受体，CDS 1和CXCR 4， 与特定信号分子的激活相关，包括Src 家族林恩激酶、RAFTK/Pyk 2、Erk 1/2和p38 MAP激酶和Fas-配体。 这些数据表明，促炎和凋亡事件可能发生，由于 通过“无辜的旁观者”双重暴露于HCV和HIV包膜蛋白 机制该建议旨在描述IL-8的分子机制 HCV E2和HIV gp 120引起的细胞凋亡的诱导和程序。一 提出了一种集中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，并聚集在转录激活因子， MAP激酶家族。阐明这些HCV和HIV包膜蛋白如何 与肝细胞的相互作用不仅可以加深我们对 在共感染宿主中的疾病发病机制，而且还导致靶向 治疗策略，以改善目前这种不良的预后 个体