Dominance of the CD4⁺ T helper cell response during acute resolving hepatitis a virus infection

Hepatitis A virus (HAV) infection typically resolves within 4-7 wk but symptomatic relapse occurs in up to 20% of cases. Immune mechanisms that terminate acute HAV infection, and prevent a relapse of virus replication and liver disease, are unknown. Here, patterns of T cell immunity, virus replication, and hepatocellular injury were studied in two HAV-infected chim- panzees. HAV-specific CD8⁺ T cells were either not detected in the blood or failed to display effector function until after viremia and hepatitis began to subside. The function of CD8⁺ T cells improved slowly as the cells acquired a memory phenotype but was largely restricted to production of IFN-γ In contrast, CD4⁺ T cells produced multiple cytokines when viremia first declined. Moreover, only CD4⁺ T cells responded during a transient resurgence of fecal HAV shedding. This helper response then contracted slowly over several months as HAV genomes were eliminated from liver. The findings indicate a dominant role for CD4⁺ T cells in the termination of HAV infection and, possibly, surveillance of an intrahepatic reservoir of HAV genomes that decays slowly. Rapid contraction or failure to sustain such a CD4⁺ T cell response after resolution of symptoms could increase the risk of relapsing hepatitis A.