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.
Munshi
Neru
N
Divisions of Experimental Medicine and Infectious Diseases, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, Massachusetts 02115, USA.
Balasubramanian
Anuradha
A
Koziel
Margaret
M
Ganju
Ramesh K
RK
Groopman
Jerome E
JE
D017209:Apoptosis; D045744:Cell Line, Tumor; D053222:Fas Ligand Protein; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism; D016174:Hepacivirus / Q000378:metabolism / Q000472:pathogenicity; D006526:Hepatitis C / Q000473:pathology; D022781:Hepatocytes / Q000473:pathology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D008562:Membrane Glycoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D014162:Transfection; D015854:Up-Regulation; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D015699:HIV Envelope Protein gp120; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt