Hepatitis B virus mutations associated with fulminant hepatitis induce apoptosis in primary Tupaia hepatocytes†

Pathogenesis of hepatitis B virus infection

“…Naturally occurring mutations in the context of various genotypes have been identified in the structural and non-structural genes as well as regulatory elements of the virus. The best characterized mutants are the pre-core (pre-C) stop codon mutations resulting in a loss of hepatitis B e antigen [18] , defined clusters of mutations in the core promoter resulting in enhanced viral replication [19][20][21] , and mutations in the reverse transcriptase/polymerase genes conferring resistance to antivirals [16,22] . Furthermore, several mutations in the HBV surface gene have been identified which alter the antigenicity of the viral surface proteins (HBsAg) and structure of the viral envelope [15,23] .…”

“…Some of the patients have a decrease or loss of HBeAg [39,43] . A common hallmark of core promoter mutations is the biological phenotype of enhanced viral replication in transfected hepatoma cell lines [19,21,33,[39][40][41][42][43][44] and primary hepatocytes [20] . The most prevalent mutant comprises a double mutation (A to T at nucleotide 1764 and G to A at nucleotide 1766, nucleotide numbering according to [46] located at the 3`end of enhancer Ⅱ of the basal core promotor being present in up to 80% of individuals chronically infected with HBV [47] .…”

“…Interestingly, the transmission of a high-replication strain containing two core promotor mutations and the pre-C mutation to HBVnaive patients has resulted in an outbreak of fulminant fatal hepatitis [19] . Enhanced viral replication with the concomitant increase in viral protein expression may result in a differential immune response as well as a more rapid and widespread infection in naive patients [19,20,40] . Altered viral kinetics accompanied by a more vigorous cellular immune response may be important mechanisms resulting in more severe liver injury and potentially fulminant hepatitis.…”

Viral factors and outcome of chronic hepatitis B revisited

“…An HBeAg-negative chronic hepatitis B (CHB) phase (HBeAg-negative, HBV DNA level above 2,000-20,000 IU/mL, normal/high ALT level and histological signs of CHB) occurs in patients who have achieved HBeAg seroconversion or in inactive carriers due to HBV reactivation [1]. Basal core promoter (BCP) mutations have been reported to possibly modulate HBV replication [2][3][4] and could thus impact the natural course of CHB. In addition, BCP mutations (the more common are the BCP A1762T/G1764A dual mutations) and precore G1896A mutation lead to the impairment and abolishment, respectively, of HBeAg production [5], and they have been reported in patients with HBeAg-negative CHB occurring under immune pressure to control HBV infection.…”

A Novel Target of Hepatitis B Virus Mutations: Splicing of Surface RNA * #

“…[1][2][3] Naturally occurring mutations in the context of various genotypes have been identified in the structural and nonstructural genes as well as regulatory elements of the virus. The best characterized mutants are the pre-core (pre-C) stop codon mutation resulting in a loss of hepatitis B e antigen, 4 defined clusters of mutations in the core promoter resulting in enhanced viral replication, [5][6][7] and mutations in the reverse transcriptase/polymerase conferring resistance to antivirals. 3 Furthermore, several mutations in the HBV surface gene have been identified which alter the antigenicity of the viral surface proteins (HBsAg) and structure of the viral envelope.…”