Hepatitis C and Human Immunodeficiency Virus Envelope Proteins Cooperatively Induce Hepatocytic Apoptosis via an Innocent Bystander Mechanism

We hypothesized that hepatocytes exposed to hepatitis C virus (HCV) and human immunodeficiency virus (HIV) might be injured via an “innocent bystander ” mechanism due to cell-surface binding of viral proteins. To assess this, we studied the effects of HCV envelope protein E2 and T-tropic HIV envelope glycoprotein gp120 on hepatocytes and saw potent apoptosis. Either viral protein alone did not induce this effect. HCV E2 and M-tropic HIV gp120 also induced significant apoptosis. Blocking the CXCR4 receptor led to a reduction in apoptosis. HCV E2 and HIV gp120 acted collaboratively to trigger a specific set of downstream signaling events, including up-regulation of the Fas ligand and dephosphorylation of the anti-apoptotic molecule AKT. These results suggest that hepatic injury may occur in HCV/HIV coinfection through the induction of novel downstream signaling pathways and provide a rationale for therapeutic interventions that interfere with specific receptors and signaling molecules. Hepatitis C virus (HCV) and human immunodefi-ciency virus (HIV) frequently coexist because of com-mon routes of transmission, and liver disease caused by HCV is rapidly becoming one of the most important complications in persons with HIV. Between 50 % an