Activation of cellular innate immunity during primary hepacivirus infection (VIR9P.1137)

Abstract

Abstract Hepatitis C virus (HCV) is estimated to infect 170 million people worldwide causing global morbidity and mortality. The course of infection can either lead to natural resolution or chronicity, but the factors dictating these two phenotypes are poorly understood. In this study we utilized an understudied model of HCV infection, GBV-B infection of common marmosets, to characterize acute and chronic immune responses. Plasma viremia was detectable by day-3 post-infection (p.i.) and greater than 50% of animals remained viremic beyond day-28 p.i. In general, plasma viremia was correlated with elevated serum ALT, AST, ALP and GGT. Primary GBV-B infection was also associated with mobilization of innate natural killer (NK) and myeloid dendritic cells (mDCs), as evidenced by increased surface CXCR3 ­— suggesting trafficking to tissues, and increased intracellular Ki67 expression. Indeed, NK cell and mDC frequencies increased 2- to 5-fold in the liver associated with high viral loads at day-14 p.i. Additional cell accumulation was observed in mesenteric lymph nodes and spleen. Functionally, NK cells demonstrated increased expression of intracellular perforin during acute infection, but had no obvious changes in IFN-g or TNF-a secretion. These data indicate the accumulation of innate cells occurs well before development of adaptive T and B cell responses and is associated with virus clearance, suggesting innate cells could be targeted in future vaccine and immunotherapeutic modalities.