Incubation phase of acute hepatitis B in man: Dynamic of cellular immune mechanisms

After hepatitis B virus (HBV) infection, liver injury and viral control hav e been thought to result from lysis of infected hepatocytes by virus-specif ic cytotoxic T cells. Patients are usually studied only after developing si gnificant liver injury, and so the viral and immune events during the incub ation phase of disease have not been defined. During a single-source outbre ak of HBV infection, we identified patients before the onset of symptomatic hepatitis. The dynamics of HBV replication, liver injury, and HBV-specific CD8+ and CD4+ cell responses were investigated from incubation to recovery . Although a rise in alanine transaminase (ALT) levels was present at the t ime of the initial fall in HBV-DNA levels, maximal reduction in virus level occurred before significant liver injury, Direct ex vivo quantification of HBV-specific CD4+ and CD8+ cells, by using human leukocyte antigen (HLA) c lass I tetramers and intracellular cytokine staining, showed that adaptive immune mechanisms are present during the incubation phase, at least 4 weeks before symptoms. The results suggest that the pattern of reduction in HBV replication is not directly proportional to tissue injury during acute hepa titis B in humans. Furthermore, because virus-specific immune responses and significant reductions in viral replication are seen during the incubation phase, it is likely that the immune events central to viral control occur before synptomatic disease.