NK cell activation and metabolic syndrome in a small nonhuman primate model of Hepacivirus infection

Abstract

Abstract Hepatitis C virus (HCV) infects greater than 170 million people worldwide. The disease remains a major source of global morbidity and mortality, but factors leading to resolution or chronicity remain unclear. In this study, we evaluated acute and longitudinal immune responses in an understudied model of HCV infection, GBV-B infection of common marmosets. Plasma viremia was detectable by day 3 post infection (pi) generally peaking by day 14 pi, at which point high virus titers were also found in the liver. Virus clearance was observed in all animals by day 112 pi. Elevated serum levels of ALT, AST and GGT, along with microscopic liver lesions of inflammation and fibrosis were indicative of hepatitis. Increases in serum creatine kinase, triglycerides and glucose, and decreased amylase levels suggested metabolic dysregulation. Interestingly, natural killer cells, which have been linked to bystander damage in the liver, demonstrated increased expression of perforin, Ki-67 and CXCR3 following infection, and were increased up to 5-fold in the liver by day 14 and remained elevated even after viral clearance. Generalized T cell activation was observed by day 28 pi, and GBV-B-specific responses were generally focused on NS3 peptides (IFN-γ ELISPOT) and were up to 10-fold higher in liver compared to peripheral organs. Our results suggest that early NK cell activation could play a major role in limiting hepaciviral infection in marmosets, or alternatively contribute to tissue inflammation and liver damage. Regardless, these data highlight the recapitulation of inflammation and metabolic dysfunction in a tangible small animal model for HCV and suggest innate cell targeting could be an attractive target for future therapeutics.