**2. Variations in pathogenesis**

A hallmark in the pathogenesis of HBV infection is its' variability. Among acutely infected adults, up to 65% develop a subclinical infection characterized only by the appearance of one or more viral antibodies in the blood, while another 25% develop acute resolving infection, which may or may not include a bout of hepatitis. The remaining 10% of patients develop chronic infection (i.e., the persistence of virus and virus antigens in the blood for more than 6 months). In chimpanzees [12] and woodchucks [13], acute infections are characterized by the nearly complete clearance of virus from the blood and liver followed by seroconversion from surface antigen to corresponding antibody. In this case, virus is mostly cleared by non-cytolytic cytokines (e.g., interferon gamma [IFNɣ] and tumor necrosis factor alpha [TNFα]) prior to the appearance of T and other inflammatory cells in the liver, suggesting that most virus clearance occurs prior to the development of acute hepatitis. Further work showed that CD4<sup>+</sup> and CD8+ T cells, natural killer (NK) cells, Fas, various IFNs and corresponding receptors, and the TNF receptor 1 participate in virus clearance, suggesting redundant pathways inhibit HBV replication in the liver [14]. The subsequent contribution of a T cell response appears to clear virus infected cells by cytolytic mechanisms involving Fas and granzymes. In this context, CD4+ T cells are required to prime CD8<sup>+</sup> T cells to facilitate virus elimination in acute infection [14]. When this happens in acute, resolving infection, the T cell response to HBV is vigorous, polyclonal and multi-specific, while among those who go on to develop chronic infection, adaptive immunity is relatively weak and narrowly focused, suggesting that clearance of HBV is T cell dependent. When T cell responses are not adequate, CLD may develop and progress to cirrhosis and HCC. However, CLD may spontaneously resolve at any of these stages. While the origin of this variability is not completely characterized, it is clear that the ability of the host to mount adaptive immune responses is a key element to limiting virus spread.
