Background:  HIV accelerates the course of hepatitis C virus (HCV) liver disease, although the mechanisms are unknown. We have previously demonstrated that HIV envelope glycoprotein gp120 binds to the chemokine co-receptor CXCR4 on immune cells and makes the cell sensitive to tumor necrosis factor (TNF) -related apoptosis inducing ligand (TRAIL). Since CXCR4 is expressed on fresh human hepatocytes, we questioned whether HIV gp120 signaling through CXCR4 would sensitize hepatocytes to TRAIL.

Methods:  Freshly isolated human hepatocytes and Huh7 cells were pre-treated or not with 1 µg/µL pertussis toxin, 400 nM JNK II inhibitor, or 8 µM SB203580, p38 inhibitor followed by X4 HIV gp120 for 6 hours followed by 100 ng/mL super-killer TRAIL for 18 hours. Cell viability was determined by MTS assay. Cells were also analyzed for TRAIL R2 expression by flow cytometry. Liver samples from uninfected humans or those infected with HCV, or HIV/HCV were stained with fluorescently labeled anti-TRAIL R2 antibody and analyzed by confocal microscopy.

Results:  HIV gp120 treatment induced TRAIL R2 expression on the surface of human hepatocytes. Super-killer TRAIL treatment killed 5% of untreated hepatocytes and 45% of HIV gp120 treated hepatocytes which was blocked by JNKII inhibition, but not p38 inhibitor or the G-protein inhibitor, pertussis toxin. Uninfected and HCV-infected liver samples had little TRAIL R2 expression, but HIV/HCV-infected liver had increased TRAIL R2 expression.

Conclusions:  HIV gp120 induces TRAIL R2 expression on human hepatocytes and makes previously TRAIL-insensitive hepatocytes sensitive to TRAIL-mediated apoptosis. This occurs via JNKII signaling and independent of p38 or G-protein activation. Thus, HIV may sensitize the liver to cellular injury in settings of increased TRAIL expression.