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

Abstract

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 interferongamma 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

Hepatitis B virus persistence and reactivation

“…For example, in vitro co-culture studies indicate that macrophages are capable of sensing HBV and release cytokines and chemokines only when exposed to high HBV titers 43. Activation of natural killer cells, another component of innate immunity enriched in the liver, is shown in patients who are at the stage of having detectable HBsAg50 and also in the liver of acutely infected woodchuck 4-5 weeks post-inoculation 51. The hypothesis that links this innate immune response, if it exists, to the initiation of adaptive immunity, awaits further verification.…”

Targeting Host Innate and Adaptive Immunity to Achieve the Functional Cure of Chronic Hepatitis B

“…Since the majority of immunocompetent adults can clear HBV infection spontaneously, host immune responses may play important roles in controlling HBV infection. Indeed, coordinated interplay between innate and adaptive immunity has been shown to mediate the clearance of HBV infection [ 19 , 54 , 55 ]. CHB development is associated with strong innate immune response impairment, the age of infection, and the failure of HBV-specific immune responses; thus, the rescue of exhausted T cell reactivity may represent a rational strategy for curing HBV infection [ 56 , 57 , 58 , 59 , 60 ].…”

Application of the woodchuck animal model for the treatment of hepatitis B virus-induced liver cancer

“…In the liver, innate immune response is activated within hours after experimental infection and partially inhibits WHV replication[ 46 ], although the infection expands further and reaches a peak thereafter. After a lack phase of immune response induction probably due to the “stealth-like behavior” of hepatitis viruses[ 38 , 47 ], a second, more marked, suppression of WHV replication is observed that is mediated by a non-cytolytic mechanism of viral clearance involving type I and II interferons (IFNs)[ 48 ]. IFN-α and IFN-β are most likely produced by activated PRRs after sensing of viral DNA and RNA in the liver, while IFN-γ is mainly secreted by natural killer (NK) cells.…”

“…These antiviral cytokines inhibit the transcription of viral pre-genomic RNA from the episomal, covalently-closed circular (ccc) DNA genome in the nucleus of infected hepatocytes, block its packaging into nucleocapsids, prevent viral replication through upregulation of a ribonuclease, and/or impede synthesis of viral relaxed-circular (rc) DNA within these core particles during maturation, as shown for HBV in cell culture[ 49 - 53 ]and animal models[ 54 - 56 ]. However, these antiviral cytokines do not affect the levels of WHV e and surface antigens (WHeAg and WHsAg) in the periphery of woodchucks[ 48 , 57 ]. This is followed by a cytolytic mechanism of viral clearance leading to a nearly complete loss of both serum viremia and antigenemia, as well as of intrahepatic WHV cccDNA[ 48 , 57 ].…”