Activated macrophages promote hepatitis C virus entry in a tumor necrosis factor-dependent manner

Abstract

Macrophages are critical components of the innate immune response in the liver. Chronic hepatitis C is associated with immune infiltration and the infected liver shows a significant increase in total macrophage numbers; however, their role in the viral life cycle is poorly understood. Activation of blood-derived and intrahepatic macrophages with a panel of Toll-like receptor agonists induce soluble mediators that promote hepatitis C virus (HCV) entry into polarized hepatoma cells. We identified tumor necrosis factor ? (TNF-?) as the major cytokine involved in this process. Importantly, this effect was not limited to HCV; TNF-? increased the permissivity of hepatoma cells to infection by Lassa, measles and vesicular stomatitis pseudoviruses. TNF-? induced a relocalization of tight junction protein occludin and increased the lateral diffusion speed of HCV receptor tetraspanin CD81 in polarized HepG2 cells, providing a mechanism for their increased permissivity to support HCV entry. High concentrations of HCV particles could stimulate macrophages to express TNF-?, providing a direct mechanism for the virus to promote infection. Conclusion: This study shows a new role for TNF-? to increase virus entry and highlights the potential for HCV to exploit existing innate immune responses in the liver to promote de novo infection events. © 2014 The Authors. Hepatology published by Wiley on behalf of the American Association for the Study of Liver Diseases.