Changing concept of hepatitis B virus

Abstract

Hepatitis B virus (HBV) infection is currently one of the most common chronic viral infections worldwide. Two billion people are estimated to be exposed to HBV infection once in their whole life. HBV infection causes a wide spectrum of liver disease, including acute or fulminant hepatitis, inactive carrier state, reactivation, chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). More than 420 million individuals in the world are estimated to have chronic HBV infections; 15–40% of them are at risk to die due to liver failure, or HCC. Hepatitis B virus have been classified into four serotypes by mutually exclusive point mutation in the S region of HBV DNA. Recent studies showed eight genotypes, A–H, of HBV are distinguished by a divergence > 8% and molecular evolutionary analysis in the entire genomic sequence and associated with anthropologic and human migration. One of the most important findings in HBV genotypes has distinct geographic distributions and the different clinical manifestations in each area. Genotype A is associated with chronic liver disease more frequently than genotype D which is most prevalent in the world. Genotype A is classified into three subgenotypes, A1–A3, and A1 is reported to be associated with highly prevalence of HCC in Africa with specific mutation in the precore region. Genotype E is reported by the association with progression to HBV carrier during the childhood in East Africa and genotype F and H are localized in the New World. Recent identified genotype G always co-infected with genotype A and is incapable of the processing of HBeAg. HBV genotype B and C are common in Asia and genotype C has higher disease-inducing capacity than genotype B with high positivity of HBeAg and basic core promoter mutation in Eastern countries. Moreover, genotype B is classified into two major subgenotypes, Bj and Ba. Ba is located in Asian countries except Japan and recombinated with genotype C in the core region. Interestingly, Ba is strongly associated with HCC among young generation, < 35 years. Genotype A and D are prevalent in the Middle-East and Central and South Asian countries. These data indicate that clinical differences among HBV genotypes would be attributable by infecting genome structure of HBV genotypes. To investigate these differences, we developed HBV transfection system using 1·24-fold HBV genome constructs belonging to HBV genotypes, Aa, Ae, Ba, Bj, C and D for in vitro and used SCID transgenic mice for urokinase-type plasminogen activator with human hepatocyte (chimeric mice) for in vivo. HBV DNA levels in cell lysates of Huh 7 cells were the highest for C followed by Bj and Ba, by D and Ae (P < 0·01) and the lowest by Aa (P < 0·01), whereas in culture media, they were the highest for Bj, distantly followed by Ba, C and D (P < 0·01), and further by Ae and Aa (P < 0·01). HBV Core protein was about threefold higher for D than Ae and Aa. Cellular retention in Huh 7 cells was higher for C and Ba to other genotypes. HBsAg was most abundant for Ae followed by Aa, Ba, Bj, and C and remotely by D, which was consistent with mRNA levels. The HBV DNA levels expressed in the chimeric mice were higher for C than Ae by 2 logs at 4–7 weeks postinoculation. In conclusion, virological differences in HBV genotypes were demonstrated both in tissue culture and the chimeric mice. These differences explained the different clinical manifestation of HBV infections with distinct genotypes in the host and also indicated that provision against HBV infection through blood transfusion should be considered on specific HBV genotype in each area of the world depending on the diffident clinical and virological characteristics of HBV genotypes.