Transient Interferon-Driven Natural Killer Cell Activation in Acute Hepatitis C

Acute infection with hepatitis C virus (HCV) is a rare event that can be treated successfully with direct-acting antivirals (DAAs). As natural killer (NK) cells play an important role during the natural course of acute HCV, we assessed the NK cell compartment via flow cytometry and single-cell sequencing in longitudinally sampled patients with acute HCV and compared this to healthy controls and patients with chronic HCV. At the transcriptomic level, we identified a subset of highly activated NK cells with a robust type I interferon imprint. While the population of activated NK cells vanished after DAA-mediated cure, a long-term phenotypic imprint of infection was observed in comparison to healthy controls. Collectively, these data suggest an interferon-driven rise of an activated NK cell population during acute hepatitis C that is largely restored upon viral clearance. This study provides insights into the immunological basis for successful antiviral response to hepatitis C.