Viral mutants and fulminant hepatitis. A dominant hepatitis B virus population defective in virus secretion because of several S-gene mutations from a patient with fulminant hepatitis.
Journal
Journal of pediatric gastroenterology and nutrition
Journal Volume
34
Journal Issue
4
Pages
426
Date Issued
2002
Author(s)
Abstract
A Dominant Hepatitis B Virus Population Defective in Virus Secretion Because of Several S-Gene Mutations From a Patient With Fulminant Hepatitis. Kalinina T, Riu A, Fischer L, Will H, Sterneck M. Hepatology 2001;34:385–94. Summary: Kalinina et al. isolated variants of hepatitis B virus (HBV) with enhanced replication competence and a possible defect in viral particle secretion from a patient with fulminant recurrent HBV infection after liver transplantation. Both viral features may have contributed to the severity of the disease. The aim of this study was to prove the secretion defect of these variants, to analyze the consequences, and to identify the responsible viral mutations. The variant genomes and appropriate wild-type variant hybrid genomes were characterized functionally after transfection in human hepatoma cells. Two cloned genomes and the polymerase chain reaction–amplified mixture of full-length genomes showed a block in viral particle secretion. A combination of amino acid changes in the S protein caused this block, including the mutation G145R, frequently emerging after hyperimmunoglobulin treatment. The mutations induced retention of the surface proteins in an endoplasmic reticulum–like compartment, but did not induce intracellular accumulation. The authors concluded that a dominant HBV population with a severe defect in viral particle secretion caused by mutations in the S-gene in combination with the enhanced replication competence might have contributed to the fulminant clinical course of the infection. Comments: Mei-Hwei Chang M.D. Department of Pediatrics National Taiwan University Hospital Taipei, Taiwan The mechanism of fulminant hepatitis is unclear despite previous efforts to understand it. The host, the virus, and their interaction all may play roles in the pathogenesis. Most studies have focused on investigating the viruses because the host factors are more difficult to study. In hyperendemic areas, fulminant HBV infection occurs most commonly in infants of mothers who are hepatitis B e antigen (HBeAg) negative, and antibody (anti-HBe) positive (J Pediatr 1987;111:34–9;Pediatric Res 1991;29:5–9). This suggests that maternal transmission of some pathogenic viral strains may relate to the fulminant liver damage in their infants. The roles of HBV precore gene and basal core promoter gene mutation in patients with fulminant hepatitis have been studied, with controversial conclusions. Some studies report that HBV precore gene nucleotide 1896 stop codon (TGG to TAG) mutants (N Engl J Med 1991;324:1699–704;N Engl J Med 1991;324:1705–9;Virology 1993;194:263–76) and mutation at nucleotide 1762 (A to T) and 1764 (G to A) of the basal core promoter (Ann Intern Med 1995;122:241–8) relate to fulminant HBV infection. Yet similar sequences of the precore stop codon mutant have been observed in children with acute HBV infection or in children with chronic HBV infection after HBeAg seroconversion who have later had normal liver function profiles in later studies (J Infect Dis 1995;171:776–81;J Hepatol 1998;28:915–22). Precore stop codon mutant alone probably is not sufficient to cause fulminant HBV infection in children. Double nucleotide mutation in the start codon of the pre-S2 gene, which may prevent the synthesis of this protein (Hepatology 1997;26:495–9), also may relate to the pathogenesis of fulminant HBV infection. In addition to demonstrating a wide variety of viral mutations in patients with fulminant hepatitis, functional studies of these mutant viral strains can provide further information about their replication competence compared with the wild-type. Studying other functional characteristics or defects can clarify the possible pathogenetic role of those mutants. Functional analysis of HBV precore and core promoter mutants with in vitro transfection showed replication competence with enhanced, similar, or decreased amounts of intracellular transcription intermediates and extracellular viral particles (J Virol 1994;68:1651–9;Hepatology 1998;28:1390–7;J Virol 1996;70:5845–51). However, the HBeAg concentrations produced by precore mutants or core promoter mutants were much lower than that produced by wild type. The patient described by Kalinina et al. had chronic HBeAg-negative HBV infection and received immunosuppression after liver transplantation. The fulminant, recurrent HBV infection in immunocompromised patients differs from the fulminant HBV infection in immunocompetent patients. The latter fulfills the strict definition of fulminant hepatitis with no previous liver diseases, and the HBV DNA concentrations in the liver tissues and circulation of these hosts often are very low. On the contrary, immunocompromised hosts who have fulminant, recurrent hepatitis, such as patients after liver transplantation or patients with cancer, often have increased concentrations of circulatory and liver HBV DNA after immunosuppression. The HBV S gene mutant with secretory defect, demonstrated by Kalinina et al. in a patient with fulminant, recurrent HBV infections, may not explain the massive hepatocyte damage in other patients with fulminant HBV infection who have not had previous liver disease. Further studies to prove directly the cause and effect of viral mutants in fulminant hepatitis and the viral–host interaction are necessary to clarify the mechanism of viral fulminant hepatitis.
SDGs
Other Subjects
article; genetics; hepatitis B; Hepatitis B virus; human; infant; mutation; physiology; Hepatitis B; Hepatitis B virus; Humans; Infant; Mutation; MLCS; MLOWN
Type
journal article