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Session 85 Poster Session HCV Co-Infection: Diagnosis and Pathogenesis Session Time: 4:30-6:30 pm Room 4E-F

645-M. HIV env Mediates Apoptosis of Human Hepatocytes via CXCR4 S. Vlahakis*, A. Villasis-Keever, T. Gomez, and C. V. Paya Mayo Clin., Rochester, MN Background: The course of HIV infection is frequently associated with hepatoxicity. Currently, one of the leading causes of hospital associated HIV deaths is due to liver disease. In HIV-infected patients, depletion of CD4 and CD8 T cells and neurons is mediated by the HIV envelope (env) signaling cellular apoptosis through the chemokine co-receptors. We, therefore, sought to determine if HIV env induces hepatocyte death and delineate the molecular mechanisms. Methods: Human hepatocyte cell lines HUH7, Hep3B, and HepG2 were stained with the anti-CXCR4 antibody 12G5 and analyzed by flow cytometry. HUH7 cells were incubated for 48 hours with soluble X4 env or SDF1alpha at different time points and analyzed for cell viability by MTS reduction and confocal microscopy using TUNEL staining. HUH7 cells were also incubated for 48 hours with non- and HIV-infected CD4 T cells fixed with 2% paraformaldehyde, and then analyzed for cell viability. Results: The human hepatocyte cell lines expressed the HIV chemokine co-receptor CXCR4 as demonstrated by flow cytometry (HUH7 40%, Hep3B 30%, and HepG2 20%). When incubated with soluble X4 env, HUH7 cell viability decreased by 30% compared to untreated controls. Cell death peaked at 48 hours of incubation and was confirmed to be apoptosis by TUNEL. In contrast, SDF1alpha, the natural ligand of CXCR4, did not induce hepatocyte death at the same time points. HUH7 cells were also incubated with fixed HIV infected CD4 T cells, resulting in a 40% decrease in viability compared to cells incubated with non-infected CD4 T cells. Conclusions: Our results demonstrate that human hepatocytes express the HIV chemokine receptor CXCR4 that has been implicated in HIV env-mediated death of primary T cells and neurons. In addition, soluble X4 HIV envelope and X4 HIV infected CD4 T cells induce hepatocyte apoptosis. These findings suggest that HIV env may play a key role in causing liver disease in HIV-infected patients.

©2002 9th Conference on Retroviruses and Opportunistic Infections