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.