Putative roles of hepatitis B x antigen in the pathogenesis of chronic liver disease

Abstract

Under most circumstances, hepatitis B virus (HBV) is noncytopathic. However, hepatocellular regeneration that accompanies each bout of hepatitis appears to be associated with increased integration of HBV DNA fragments expressing the virus encoded hepatitis B x antigen (HBxAg). Intrahepatic HBxAg staining correlates with the intensity and progression of chronic liver disease (CLD), and additional work has shown that HBxAg blocks immune mediated killing by Fas and by tumor necrosis factor alpha (TNFalpha). This is not only associated with the blockage of caspase activities by HBxAg, but also by the constitutive stimulation of hepatoprotective pathways, such as nuclear factor kappa B (NF-kappaB), phosphoinositol 3-kinase (PI3K), and beta-catenin (beta-catenin). HBxAg also appears to promote fibrogenesis, by stimulating the production of fibronectin. HBxAg also stimulates the production and activity of transforming growth factor beta1 (TGFbeta1) by several mechanisms, thereby promoting the profibrogenic and tumorigenic properties of this important cytokine. In addition, HBxAg appears to remodel the extracellular matrix (ECM) by altering the expression of several matrix metalloproteinases (MMPs), which may promote tumor metastasis. Hence, HBxAg appears to promote chronic infection by preventing immune mediated apoptosis of infected hepatocytes, by promoting the establishment and persistence of fibrosis and cirrhosis preceding the development of HCC, and by promoting the remodeling of EMC during tumor progression.

Fig. 1

Model of the HBV DNA genome as it exists in the virus particle. Note that the ends of the genome, at direct repeats 1 and 2 (DR1 and DR2), respectively, are both within the X region. Integration events into host DNA often occur in or around the DR1 sequences of HBV so that the X gene is the most frequent integrated portion of HBV DNA.

Fig. 2

Some of the mechanisms whereby HBxAg confers resistance to immune mediated apoptosis. The pathways shown highlight TNFα Fas, β-catenin and TGFβ1 signaling.

Fig. 3

Summary of various pathways whereby HBxAg may contribute importantly to the development of fibrosis and cirrhosis during CLD.

Fig. 4

Proposed changes in TGFβ1 signaling by HBxAg. Normally, TGFβ1 signaling maintains homeostatsis by acting as a negative growth regulator in the liver, but during chronic viral infection, HBxAg overrides this negative growth regulation by activating additional signaling pathways that block negative growth regulation and stimulate hepatocellular growth and survival, which may be early steps in hepatocarcinogenesis (modified from [122]).