Clinical-liver, pancreas, and biliary tractSequence variation upstream of precore translation initiation codon reduces hepatitis B virus e antigen production☆
Section snippets
Subjects
Blood was obtained, with informed consent, from 45 black Africans. Eighteen were hepatitis B surface antigen (HBsAg)-positive asymptomatic carriers with normal serum alanine aminotransferase (ALT) levels. The HBeAg status of these patients is summarized in Table 1. Five patients had acute hepatitis. The ALT levels in these patients ranged from 799 to 4747 IU/L. One patient with fulminant hepatitis was a woman aged 32 years with an ALT level of 979 IU/L. In addition, 21 children were studied.
The SA mutations are present throughout the course of infection
Many individuals described in a previous study had seroconverted to anti-HBe and contained core promoter mutations, and a subset had developed hepatocellular carcinoma.8 Thus, whether the sequence changes at 1809–1812 were stable traits or whether they represented adaptive change under the immune pressure of anti-HBe, similar to that observed with core promoter and precore mutations, could not be established. For this reason, we sequenced HBV isolates from 6 patients with acute hepatitis (1
Discussion
The sequence around the precore initiation codon is conserved in all the 8 known genotypes as 5′-AGCACCC-3′ (nucleotides 1808–1817).28 This sequence conforms to the optimal context for translational initiation, the so-called Kozak sequence (5′-GCCA/GCCG-3′).15, 24 In contrast, many SA HBV strains, which belong to a subgroup of genotype A,8, 18, 19, 20 harbor point mutations at 1809–1812.8 Such HBV variants have also been found occasionally in other parts of the world.29, 30, 31 The most
Acknowledgements
The authors thank Professor R. Bhimma of the Department of Paediatrics & Child Health, Nelson R. Mandela School of Medicine, University of Natal, Durban, South Africa, for providing the serum samples from children for analysis.
References (41)
- et al.
Mutation preventing formation of the hepatitis B e antigen in patients with chronic hepatitis B infection
Lancet
(1989) - et al.
Active hepatitis B virus replication in the presence of anti-HBe is associated with viral variants containing an inactive pre-C region
Virology
(1990) Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes
Cell
(1986)At least six nucleotides preceding the AUG initiator codon enhance translation in mammalian cells
J Mol Biol
(1987)- et al.
Characterization of proteinuria in asymptomatic family members and household contacts of children with hepatitis B virus-associated membranous nephropathy
Am J Kidney Dis
(2001) - et al.
Replication capacities of natural and artificial precore stop codon mutants of hepatitis B virusrelevance of pregenome encapsidation signal
Virology
(1992) Initiation of translation in prokaryotes and eukaryotes
Gene
(1999)- et al.
Expression mechanism of the hepatitis B virus (HBV) C gene and biosynthesis of HBeAg antigen
Virology
(1989) - et al.
In vitro and in vivo replication capacity of the precore region defective hepatitis B virus variants
J Hepatol
(1991) - et al.
Precore and contiguous regions of hepatitis B virus in liver transplantation for end-stage hepatitis B
Gastroenterology
(1994)
Host responses to hepatitis-B infection in patients with primary hepatic carcinoma and their familiesA case/control study in Senegal, West Africa
Lancet
Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B
Gastroenterology
Geographic distribution of hepatitis B virus (HBV) genotype in patients with chronic HBV infection in Japan
Hepatology
HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C
Hepatology
Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease
Hepatology
Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C
Gastroenterology
Hepatitis B virus
New specificities in Australia antigen positive sera distinct from the Le Bouvier determinants
J Immunol
Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero?
Proc Natl Acad Sci U S A
The secreted hepatitis B precore antigen can modulate the immune response to the nucleocapsida mechanism for persistence
J Immunol
Cited by (67)
Construction of replication competent plasmids of hepatitis B virus subgenotypes A1, A2 and D3 with authentic endogenous promoters
2014, Journal of Virological MethodsCitation Excerpt :In a clinical setting, patients infected with subgenotype A1 had significantly lower serum HBV DNA levels compared to those infected with subgenotype A2 or genotype D, regardless of HBeAg status (Guarnieri et al., 2006; Kramvis et al., 1997; Tanaka et al., 2004). When TCAT mutations between 1809 and 1812, which are characteristic of subgenotype A1, were introduced into subgenotype A2, there was a significant decrease in HBeAg translation in transfected cells (Ahn et al., 2003; Baptista et al., 1999). The intracellular accumulation of replicative intermediates and HBcAg seen in subgenotype A1 may play a role in inducing liver damage (Sugiyama et al., 2006) and may account for the rapid disease progression and high rates for HCC seen in individuals infected with this subgenotype (Kew, 1994; Kew et al., 2005; Kramvis et al., 1998).
Molecular epidemiology of Hepatitis B virus in Córdoba, Argentina
2014, Journal of Clinical VirologyCitation Excerpt :Several mutations have been described in different regions of the HBV genome associated with varied forms of disease progression and response to therapy. There are evidences that amino acid substitutions within the hepatitis B surface antigen (HBsAg) [24], the HBV polymerase domains [25,26] and the precore (pC) or basal core promoter (BCP) region [27–29] are of clinical importance. The epidemiology of these HBV mutants has been widely studied principally in countries where HBV is endemic.
Distinct mutant hepatitis B virus genomes, with alterations in all four open reading frames, in a single South African hepatocellular carcinoma patient
2012, Virus ResearchCitation Excerpt :Three of the five clones had 1888A, which is characteristic of subgenotype A1, but all clones had 1809GCAT1812 instead of 1809TCAT1812 at the Kozak sequence preceding the precore start codon at position 1814, which is frequently found in subgenotype A1 (Kramvis et al., 2008). Strains with 1809TCAT1812 express moderately reduced levels of HBeAg relative to strains with 1809GCAC1812 (Ahn et al., 2003) and thus one would expect the clones from HCC18 to express HBeAg, although this could not be confirmed because of depletion of the serum for further analyses. The five clones had both common and unique features.
Hepatitis B Virus Research in South Africa
2022, Viruses
- ☆
Supported by a grant from the Brain Korea 21 Project for Medical Science (to S.H.A.); Lifespan Research Funds; grants CA35711, AA20169, p20RR15578, R13 AI5224101, AI54535, and DK62857 from the National Institutes of Health; and Ernst-Jung-Stiftung, Hamburg, Germany. J.L. is a Liver Scholar from the American Liver Foundation.