Activated Macrophages Promote Hepatitis C Virus Entry in a Tumor Necrosis Factor-Dependent Manner

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 hepati-tis C virus (HCV) entry into polarized hepatoma cells. We identified tumor necrosis fac-tor a (TNF-a) as the major cytokine involved in this process. Importantly, this effect was not limited to HCV; TNF-a increased the permissivity of hepatoma cells to infection by Lassa, measles and vesicular stomatitis pseudoviruses. TNF-a 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 stimu-late macrophages to express TNF-a, providing a direct mechanism for the virus to pro-mote infection. Conclusion: This study shows a new role for TNF-a to increase virus entry and highlights the potential for HCV to exploit existing innate immune response