Molecular mechanism of hepatic injury in coinfection with hepatitis C virus and HIV.
We have previously shown that hepatocytes exposed to hepatitis C virus (HCV) and human immunodeficiency virus (HIV) envelope proteins undergo apoptosis. In this article, we further elucidate the signaling mechanisms that mediate this effect. We found that, in human hepatocellular carcinoma (HepG2) cells, HCV E2 protein and HIV glycoprotein (gp) 120 significantly up-regulated the Fas ligand (FasL) and enhanced the formation of the Fas death-inducing signaling complex downstream of Fas receptor activation. Moreover, after stimulation with HCV E2 and HIV gp120, enhanced expression of caspases 2 and 7 and increased caspase 3 activity were observed. In addition, we showed up-regulation of the proapoptotic molecule Bid and its association with caspase 8 after treatment with these envelope proteins. We also found that HCV E2 and HIV gp120 induced a partial translocation of Bid to the mitochondria, which resulted in the release of cytochrome C and the apoptosis-inducing factor. Thus, the results of this study suggest that FasL and Bid play an important role in HCV and HIV envelope protein-induced apoptosis.
Balasubramanian
Anuradha
A
Division of Experimental Medicine and Infectious Disease, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, MA 02115, USA.
Koziel
Margaret
M
Groopman
Jerome E
JE
Ganju
Ramesh K
RK
D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism; D006678:HIV / Q000502:physiology*; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology; D015658:HIV Infections / Q000150:complications / Q000473:pathology*; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000150:complications / Q000473:pathology*; D022781:Hepatocytes / Q000473:pathology; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000473:pathology*; D008930:Mitochondria, Liver / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation; D014759:Viral Envelope Proteins / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D053418:Death Domain Receptor Signaling Adaptor Proteins; C491901:FAS protein, human; D053222:Fas Ligand Protein; D015699:HIV Envelope Protein gp120; C495382:HIV envelope protein gp120 (254-274); D010446:Peptide Fragments; D014759:Viral Envelope Proteins; D019014:fas Receptor; C091015:glycoprotein E2, Hepatitis C virus; D053148:Caspase 3