The role of virus-specific T cell immunity in the pathogenesis of acute and chronic Hepatitis B virus infection

Hepatitis B virus infection is a major cause of morbidity and mortality worldwide, but is of low endemicity in the UK, and outbreaks are rare. I report here a large outbreak of HBV infection, in which 57 of 356 patients and staff of an alternative medical clinic had markers of exposure to the virus. Using molecular sequencing and phylogenetic analysis 30 of 33 individuals with active infection were shown to have been infected from a common source. Infection was linked to a form of acupuncture, and the risk of infection was correlated with the number and timing of treatments. The identification of patients prior to the onset of clinical disease provided a unique opportunity to study immune responses during the early phase of hepatitis B. HBV is non- cytopathic, and early host-virus interactions have been thought to be fundamental in determining disease outcome. Using new techniques to directly quantify specific cell populations, it was found that components of the innate and adaptive immune response, including HBV-specific CD8+ and CD4+ cells, were present in the circulation weeks before clinical disease, and that maximal reductions in circulating virus also occurred before the onset of jaundice. These findings were extended to a longitudinal comparison of CDS responses in patients with resolved or chronic HBV infection, characterised according to the degree of viral control and liver injury. Virus-specific CD8+ cells were shown to persist in the circulation, years after resolution of acute infection, hi chronic infection the HBV-specific CD8+ cell responses was found not simply to be a weak version of that seen in acute disease, histead, a completely different epitope hierarchy was found, with dominance of epitopes which were usually sub-dominant in acute disease. The findings might be of relevance to the development of therapeutic vaccines for chronic hepatitis B