Innate and adaptive immunity associated with resolution of acute woodchuck hepatitis virus infection in adult woodchucks

Viral and/or host factors that are directly responsible for the acute versus chronic outcome of hepatitis B virus (HBV) infection have not been identified yet. Information on immune response during the early stages of HBV infection in humans is mainly derived from blood samples of patients with acute hepatitis B (AHB), which are usually obtained after the onset of clinical symptoms. Features of intrahepatic immune response in these patients are less studied due to the difficulty of obtaining multiple liver biopsies. Woodchuck hepatitis virus (WHV) infection in woodchucks is a model for HBV infection in humans. In the present study, five adult woodchucks were experimentally infected with WHV and then followed for 18 weeks. Blood and liver tissues were frequently collected for assaying markers of WHV replication and innate and adaptive immune responses. Liver tissues were further analyzed for pathological changes and stained for important immune cell subsets and cytokines. The increase and subsequent decline of viral replication markers in serum and liver, the elicitation of antibodies against viral proteins, and the induction of virus-specific T-cell responses indicated eventual resolution of acute WHV infection in all animals. Intrahepatic innate immune makers stayed unchanged immediately after the infection, but increased markedly during resolution, as determined by changes in transcript levels. The presence of interferon-gamma and expression of natural killer (NK) cell markers suggested that a non-cytolytic response mechanism is involved in the initial viral control in liver. This was followed by the expression of T-cell markers and cytolytic effector molecules, indicating the induction of a cytolytic response mechanism. Parallel increases in regulatory T-cell markers suggested that this cell subset participates in the overall immune cell infiltration in liver and/or has a role in regulating AHB induced by the cytolytic response mechanism. Since the transcript levels of immune cell markers in blood, when detectable, were lower than in liver, and the kinetics, except for NK-cells and interferon-gamma, did not correlate well with their intrahepatic expression, this further indicated enrichment of immune cells within liver. Conclusion: The coordinated interplay of innate and adaptive immunity mediates viral clearance in the woodchuck animal model of HBV infection. The initial presence of NK-cell associated interferon-gamma response points to an important role of this cytokine in HBV resolution. Author summary Hepatitis B virus (HBV) is a major public health concern and 257 million chronic carriers worldwide are at risk of developing serious liver disorders. Current treatment options for chronic hepatitis B (CHB) are rarely inducing viral clearance. HBV infection in immunocompetent adults is mostly asymptomatic, with a less than 5% chance of progressing to chronic infection. Contrary, more than 95% of infants infected with HBV at birth or during early childhood develop chronic infection. The viral and host factors directly deciding over the acute versus chronic outcome are largely unknown. Understanding the features of innate and adaptive immune responses during acute, self-limiting HBV infection will aid the understanding of underlying mechanisms responsible for HBV resolution, and thus support the design of immunomodulatory drugs for treatment of CHB. However, studying acute hepatitis B (AHB) in humans is challenging due to its asymptomatic nature and the limitations in obtaining multiple liver biopsies. Infection of adult woodchucks with the HBV-like woodchuck hepatitis virus (WHV) is a suitable model for studying AHB. Our comprehensive work describes the kinetics of viral replication and associated innate and adaptive immune responses, both in liver and blood, during resolution of AHB in the woodchuck model.