Immune effectors required for hepatitis B virus clearance

Abstract

To better define the mechanism(s) likely responsible for viral clearance during hepatitis B virus (HBV) infection, viral clearance was studied in a panel of immunodeficient mouse strains that were hydrodynamically transfected with a plasmid containing a replication-competent copy of the HBV genome. Neither B cells nor perforin were required to clear the viral DNA transcriptional template from the liver. In contrast, the template persisted for at least 60 days at high levels in NOD/Scid mice and at lower levels in the absence of CD4 + and CD8 + T cells, NK cells, Fas, IFN-gamma (IFN-γ), IFN-alpha/beta receptor (IFN-α/βR1), and TNF receptor 1 (TNFR1), indicating that each of these effectors was required to eliminate the transcriptional template from the liver. Interestingly, viral replication was ultimately terminated in all lineages except the NOD/Scid mice, suggesting the existence of redundant pathways that inhibit HBV replication. Finally, induction of a CD8 + T cell response in these animals depended on the presence of CD4 + T cells. These results are consistent with a model in which CD4 + T cells serve as master regulators of the adaptive immune response to HBV; CD8 + T cells are the key cellular effectors mediating HBV clearance from the liver, apparently by a Fas-dependent, perforinindependent process in which NK cells, IFN-γ, TNFR1, and IFN-α/βR play supporting roles. These results provide insight into the complexity of the systems involved in HBV clearance, and they suggest unique directions for analysis of the mechanism(s) responsible for HBV persistence.H epatitis B virus (HBV) is a noncytopathic human hepadnavirus that causes acute and chronic hepatitis and hepatocellular carcinoma (1). Approximately 350 million people worldwide are chronically infected by HBV, which greatly increases the risk of hepatocellular carcinoma (HCC) and causes more than 1 million deaths annually (2). Because HBV is not infectious in small animal or tissue culture models, systematic examination of the host-virus interactions during HBV infection has been difficult. The full spectrum of immunological requirements for HBV clearance is not completely defined.Our current understanding is based to a large extent on comparison of the immune responses mounted against HBV in patients who clear and who fail to clear HBV (3), experiments in which potential effectors of clearance (e.g., HBsAg-specific CD8 + T cells, recombinant IFN-γ and TNF-α) have been adoptively transferred to or induced in HBV transgenic mice (4-8), and a limited number of experiments conducted in HBVinfected chimpanzees (9, 10, 18). Collectively, these studies have led to the current model for clearance of acute HBV infection, namely (i) that viral clearance during HBV infection is associated with entry of CD8 + T cells into the liver, the production of IFN-γ, and the induction of inflammatory liver disease (reviewed in ref.3); (ii) that IFN-γ production, viral clearance, and liver disease are all impaired in the absence of CD8 + T cells (11); and (iii) that noncy...

Granzyme H of Cytotoxic Lymphocytes Is Required for Clearance of the Hepatitis B Virus through Cleavage of the Hepatitis B Virus X Protein

“…This observation and our data imply that innate effector NK cells play an essential role in the elimination of HBV infection. However, this notion was not achieved by NK cell-and perforin-deficient mouse strains with an HBV infection model (20). This may be because the mouse model cannot mimic real HBV infection in humans.…”

Overcoming HBV immune tolerance to eliminate HBsAg-positive hepatocytes via pre-administration of GM-CSF as a novel adjuvant for a hepatitis B vaccine in HBV transgenic mice

“…12,49 In this regard, HBV-specific CD8 1 T cells are the key effector cells that mediate the clearance of HBsAg-positive hepatocytes from the liver. 50 IFN-c-and TNF-a-producing CD81 T cells have been demonstrated to contribute to the antiviral immune response through cytolytic and non-cytolytic pathways in the HBV-transgenic mouse model. [51][52][53] In our study, 33GM-CSF1rHBVvac significantly enhanced IFN-c secretion by CD8 1 T cells (Tc1) and induced a strong specific CTL response (Figure 2) resulting in the elimination of a major proportion of HBsAg-positive hepatocytes ( Figure 5).…”

Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model

“…34 TNF-a has been described as potentially having a potentially modulating effect on HBV gene expression 35,36 and as being a key immune effector in HBV clearance in a study of a panel of immune effector-deficient mouse strains. 16,37 As an innate cytokine, TNF-a causes iMATE formation, which facilitates the expansion of the cytotoxic T-lymphocyte population against HBV. 31 Clinically, blockage of TNF-a with anti-TNF has been widely used in many immune-mediated diseases, including rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis and psoriatic arthritis.…”