Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 209, Issue 8, Pages 1481-1492Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20111906
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Funding
- Public Health Service [R37-AI028433]
- National Institutes of Health (NIH) [U19 AI40035, OD011095, P51 RR13986]
- NIH (Office of Research Infrastructure Programs/OD) [P51 OD011133]
- Research Facilities Improvement Program [C06 RR12087, C06RR16228]
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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 chimpanzees. 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-gamma. 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.
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