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）本提案的主要目标是