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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
3R01DA015008-02S1
Application #
6657216
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Khalsa, Jagjitsingh H
Project Start
2001-09-30
Project End
2006-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
2
Fiscal Year
2002
Total Cost
$85,000
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
Zhang, Xuefeng; Yu, Jinlong; Kuzontkoski, Paula M et al. (2012) Slit2/Robo4 signaling modulates HIV-1 gp120-induced lymphatic hyperpermeability. PLoS Pathog 8:e1002461
Zhang, X; Maor, Y; Wang, J F et al. (2010) Endocannabinoid-like N-arachidonoyl serine is a novel pro-angiogenic mediator. Br J Pharmacol 160:1583-94
Balasubramanian, Anuradha; Ganju, Ramesh K; Groopman, Jerome E (2006) Signal transducer and activator of transcription factor 1 mediates apoptosis induced by hepatitis C virus and HIV envelope proteins in hepatocytes. J Infect Dis 194:670-81
Ghosh, Sharmistha; Preet, Anju; Groopman, Jerome E et al. (2006) Cannabinoid receptor CB2 modulates the CXCL12/CXCR4-mediated chemotaxis of T lymphocytes. Mol Immunol 43:2169-79
Balasubramanian, Anuradha; Munshi, Neru; Koziel, Margaret J et al. (2005) Structural proteins of Hepatitis C virus induce interleukin 8 production and apoptosis in human endothelial cells. J Gen Virol 86:3291-301
Balasubramanian, Anuradha; Koziel, Margaret; Groopman, Jerome E et al. (2005) Molecular mechanism of hepatic injury in coinfection with hepatitis C virus and HIV. Clin Infect Dis 41 Suppl 1:S32-7
Zhang, Xuefeng; Wang, Jian Feng; Chandran, Bala et al. (2005) Kaposi's sarcoma-associated herpesvirus activation of vascular endothelial growth factor receptor 3 alters endothelial function and enhances infection. J Biol Chem 280:26216-24
Munshi, Neru; Balasubramanian, Anuradha; Koziel, Margaret et al. (2003) Hepatitis C and human immunodeficiency virus envelope proteins cooperatively induce hepatocytic apoptosis via an innocent bystander mechanism. J Infect Dis 188:1192-204
Balasubramanian, Anuradha; Ganju, Ramesh K; Groopman, Jerome E (2003) Hepatitis C virus and HIV envelope proteins collaboratively mediate interleukin-8 secretion through activation of p38 MAP kinase and SHP2 in hepatocytes. J Biol Chem 278:35755-66