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: 6450551
• 负责人: JEROME E GROOPMAN
• 金额: $ 34万
• 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/6450551
• 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）该提案的主要目的是 检查丙型肝炎病毒（HCV）和人类免疫缺陷病毒如何 （HIV）信封蛋白可以协同作用以触发信号事件 这有助于肝细胞炎症和凋亡。与艾滋病毒共同感染 HCV赋予了预后不佳的情况，并具有渐进的肝功能障碍 通常导致肝硬化和死亡。静脉吸毒者和 血友病患者的共感染率很高，并且面对这种严峻的结果。 为什么共感染的宿主具有如此高的进行性肝病率？这 HCV相关肝炎的发病机理被认为部分归因于 免疫介导的炎症以及直接感染的影响 肝细胞。我们的初步数据提出了一种新颖的第三个潜在机制 肝炎和凋亡。我们在HEP​​G2细胞和原发性中观察到 与HCV包膜蛋白E2治疗的肝细胞结合 使用HIV GPL20，诱导炎症趋化因子白介素-8（IL-8），并且 触发凋亡。这些功能结果发生在纳摩尔 E2和GP 120的浓度与kD相对应 配体与其各自受体CDS1和CXCR4结合，为 与特定信号分子的激活相关，包括SRC 家族Lyn激酶，RAFTK/PYK2，ERKL/2和P38 MAP激酶以及FAS-Ligans。 这些数据表明促炎和凋亡事件可能是由于 通过“无辜旁观者”双重接触HCV和HIV信封蛋白 机制。该提议旨在表征IL-8的分子机制 HCV E2和HIV GPL20引起的诱导和凋亡程序。一个 专注的实验方法提出了描述信号事件 起源于特定细胞表面受体，通过 中间信号分子，并收敛于转录激活因子 地图激酶家族。阐明这些HCV和HIV包膜蛋白如何 与肝细胞互动不仅可以进一步我们对 共同感染宿主的疾病发病机理，但也导致了目标 改善此类预后不佳的治疗策略 个人。