Hepatitis B virus infection, the immune response and hepatocellular carcinoma.
More than 250 million people worldwide are chronically infected with the hepatitis B virus (HBV) and have a 200-fold increased risk of developing hepatocellular carcinoma (HCC). This is one of the most common cancers in the world with a geographical distribution highest in areas where HBV is endemic. A number of molecular mechanisms have been proposed to explain this correlation including an acutely transforming viral oncogene; chromosomal aberrations due to HBV integration (i.e. deletions, translocations, duplications); activation of cellular proto-oncogenes; inactivation of cellular anti-oncogenes; and transactivation of cellular genes by HBV gene products. HCC usually develops only after 20-30 years of persistent HBV infection accompanied by hepatocyte necrosis, inflammation and regenerative hyperplasia. Because HBV is not directly cytopathic, liver injury must be immune mediated. Factors that predispose HBV-infected individuals to develop HCC are chronicity, an immune response and liver injury rather than a direct genetic event. Hepatic injury and continuous hepatocyte regeneration may allow an accumulation of multiple mutational events sufficient for the emergence of HCC. Pathways which lead to chronicity, the immune response during HBV infection, mechanisms of pathogenesis and methods to prevent HBV infection are all relevant to the development of HCC. Recent studies characterizing the humoral and cellular immune responses in patients chronically infected with HBV and transgenic mouse models of HBV-specific immune tolerance and pathogenesis are providing new insights into the complex association between HBV infection and HCC.
Milich
D R
DR
Department of Molecular Biology, Scripps Research Institute, La Jolla, CA 92037, USA.
Jones
J
J
Hughes
J
J
Maruyama
T
T
D000818:Animals; D000917:Antibody Formation; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000276:immunology* / Q000821:virology; D004195:Disease Models, Animal; D006509:Hepatitis B / Q000150:complications / Q000453:epidemiology / Q000276:immunology*; D006515:Hepatitis B virus / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000453:epidemiology / Q000276:immunology* / Q000821:virology; D008114:Liver Neoplasms, Experimental / Q000276:immunology* / Q000821:virology