NK cell responses during direct-acting antiviral treatment of chronic hepatitis C virus infection

Chronic viral infections, such as chronic hepatitis C virus (HCV) infection, are known to cause immune cell exhaustion, including alterations in NK cell phenotype and function. Novel interferon-free treatment strategies against HCV, based on direct-acting antivirals (DAAs), offer the opportunity to study whether rapid elimination of a chronic virus leads to restoration of the phenotype and functional capacity of NK cells. Here, we followed 26 chronic HCV patients before, during, and after DAA treatment. Out of these patients, two-third cleared the virus whereas a third experienced a viral relapse after treatment cessation. We show that viral loads and levels of liver enzymes rapidly declined upon DAA treatment initiation and that this was accompanied with fluctuating dynamics in absolute lymphocyte counts as well as NK cell counts. We further observed changes in NK cell surface marker expression comparing chronic HCV patients at baseline with healthy controls, including lower NK cell diversity. Further phenotypic alternations occurred during the course of DAA treatment. However, the NK cell diversity remained low even after the virus had been cleared. Intriguingly, NK cells from patients that went on to clear HCV after DAA treatment exhibited a higher level of activation and were more potent producers of cytokines as compared to NK cells from patients experiencing a viral relapse. Taken together, the NK cell phenotype and function improves during successful DAA treatment. However, lower NK cell diversity appears to be a persistent feature after recovery from chronic HCV infection.