HCV persistence and immune evasion in the absence of memory T cell help

Spontaneous resolution of hepatitis C virus (HCV) infection in humans usually affords long-term immunity to persistent viremia and associated liver diseases. Here, we report that memory CD4+ T cells are essential for this protection. Antibody-mediated depletion of CD4+ T cells before reinfection of two immune chimpanzees resulted in persistent, low-level viremia despite functional intrahepatic memory CD8+ T cell responses. Incomplete control of HCV replication by memory CD8+ T cells in the absence of adequate CD4+ T cell help was associated with emergence of viral escape mutations in class I major histocompatibility complex-restricted epitopes and failure to resolve HCV infection.