Hiv Mono-Infection Is Associated With An Impaired Anti-Hepatitis C Virus Activity Of Natural Killer Cells

Objective:Hepatitis C virus (HCV) infection in HIV(+) patients is associated with faster liver disease progression compared with HCV mono-infection. HIV-associated immune defects are considered to play an important role in this context. Here, we analyzed the effects of HIV infection on natural killer (NK)-cell-mediated anti-HCV activity.Design:NK cell phenotype and interferon gamma (IFN-) production, NK cell-mediated inhibition of HCV replication and CD4(+) T-cell/NK cell interactions were studied in treatment naive HIV (n=22), and HIV patients under combined antiretroviral therapy (n=29), compared with healthy controls (n=20).Methods:NK cell-mediated inhibition of HCV replication was analyzed using the HuH7(A2)HCVreplicon model. IFN- production of NK cells as well as interleukin-2 secretion of CD4(+) T lymphocytes were studied by flow cytometry.Results:Peripheral blood mononuclear cells from HIV(+) patients displayed a significantly impaired anti-HCV activity, irrespective of combined antiretroviral therapy. This could in part be explained by HIV-associated decline in NK cell numbers. In addition, NK cell IFN- production was significantly impaired in HIV infection. Accordingly, we found low frequency of IFN-(+) NK cells in HIV(+) patients to be associated with ineffective inhibition of HCV replication. Finally, we show that CD4(+) T-cell-mediated stimulation of NK cell IFN- production was dysregulated in HIV infection with an impaired interleukin-2 response of NK cells.Conclusion:HIV infection has a strong suppressive effect on anti-HCV activity of NK cells. This may contribute to low spontaneous clearance rate and accelerated progression of HCV-associated liver disease observed in HIV(+) patients.