Hepatitis C virus (HCV)-specific adaptive immune response in (A) acute-resolving and (B) acute-persistent HCV infection. (A) In acute-resolving HCV infection, multi-specific, and vigorous HCV-specific CD4+ and CD8+ T cells are primed, and plasma cells produce broadly neutralizing antibodies (bnAbs). After viral clearance, memory cells (expressing, e.g., CD127) are maintained. (B) In acute-persistent HCV infection, the initial HCV-specific adaptive immune response is similar to acute-resolving infection, however, CD4+ T cells are rapidly lost, CD8+ T cells exhaust (expressing, e.g., PD-1), and viral escape mutations abrogate recognition by HCV-specific CD8+ T cells and nAbs. Host genetic background, including HLA class I and II alleles, as well as ERAP allotypes, might impact dichotomous outcome. Graphic elements were taken and modified from a Servier Medical Art template licensed under a Creative Commons Attribution 3.0 Unported License (CC BY 3.0) (https://smart.servier.com).