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P114: Immunoglobulin purified from antibody associated virus from hepatitis C viraemic sera exhibit selective targeting of homologous HCV genotype

IFN-g production and surface expression of NKp46 and NKG2D was measured via flow cytometry. Anti-fibrotic NK cell activity was studied by analyzing NK cell degranulation (CD107a) and induction of target cell apoptosis (caspase-3) following coculture with primary human hepatic stellate cells (hHSC). RESULTS: In contrast to healthy individuals, resting NK cells from HCV infected patients displayed significantly reduced antiviral activity after incubation at 5% or 1% O2. When cytokine-activated NK cells were observed, antiviral activity of healthy NK cells was reduced only after incubation at 1% O2, while HCV NK cells responded already at 5% O2 culture conditions. In line with that finding we observed significantly reduced IFN-g secretion of resting and activated HCV NK cells cultured under hypoxic conditions. Of note, hypoxia-induced reduction of IFN-g production was also observed in intrahepatic NK cells. Next, we found that peripheral and intrahepatic NK cells from HCV patients displayed significantly reduced expression levels of the NK cell receptors NKp46 and NKG2D when cultured at 5% and 1% O2, whereas no such effects were observed for NK cells from healthy donors. However, neither in healthy controls nor HCV infected donors anti-fibrotic NK cell activity was affected by low oxygen tension. CONCLUSIONS: Taken together, our results indicate that in HCV infected patients, anti-viral but not anti-fibrotic activity of NK cells is markedly reduced under the low oxygen tension levels which are typical for liver tissue. Importantly, this held true also for intrahepatic NK cells. Thus, low oxygen tension in the liver tissue must be considered as a novel additional mechanism contributing to insufficient intrahepatic anti-viral immune responses in chronic hepatitis C. Transferring experimental systems to hypoxic (or liver-normoxic) conditions is a new approach to gain insights into the physiological function of innate immunity against HCV.