A hepatitis B virus mutant with a new hepatocyte nuclear factor 1 binding site emerging in transplant-transmitted fulminant hepatitis B

Abstract

chronic HBV infection is thought to be immune-mediated, a Hepatitis B virus (HBV) DNA was cloned from serum direct cytopathic role for HBV is postulated in immunosupof a heart transplant recipient who died from fulminant pressed transplantation recipients, especially in patients hepatitis B transmitted by the donor. Restriction enwith histological features of fibrosing cholestatic hepatitis 1 zyme analyses of the clones obtained by conventional and steatoviral or fibroviral hepatitis B.2 In these patients cloning yielded six HBV variants: a major species (pF-1) high levels of viral nucleic acids and accumulation in the representing 88% and five minor species (pF-2 to pF-6), cytoplasm of hepatocytes of the large hepatitis B surface antieach representing 2% to 4% of the clones. The complete gen (HBsAg) have been observed. 3 Various mutations in the nucleotide sequence of these six variants revealed that HBV genome have been implicated in the severe clinical five of the six viral genomes, including pF-1, carried a course of subfulminant or fulminant HBV infection. 4 Among novel 11 base pair (bp) insertion in the core promoter these, mutations resulting in a hepatitis B e antigen (HBeAg) region as well as an 18 bp and an 108 bp in-frame deletion negative phenotype because of interference with the expresin the pre-S1 region not present in the donor. One gesion of HBeAg at either the translational level, as in precore nome was identical to the sequence of the donor. Funcstop codon mutants, [5][6][7][8][9][10][11][12] or at the transcriptional level, as in tional analyses of HBV clones generated by in vitro mucore promoter mutants, 13,14 have been associated with fulmitagenesis and cassette exchange showed that the 11 bp nant and severe acute hepatitis as well as with recurrent insertion is a strong binding site for hepatocyte nuclear HBV infection after liver transplantation [15][16][17][18][19] or fatal HBV factor 1 (HNF-1). In transient transfection experiments, reactivation following cytotoxic treatment. 20 However, other the novel HNF-1 sequence motif was shown to result in studies suggest that fulminant hepatitis B is not caused by enhanced viral replication. Immunohistochemical anala specific genomic mutation 21 and show that the mutations yses revealed high levels of cytoplasmic and nuclear described above are also found in patients with acute selfhepatitis B core antigen (HBcAg) and only scattered heplimited or chronic hepatitis B as well as in asymptomatic atitis B surface antigen (HBsAg) expression in the liver.HBV infection. 12,22-28The data in our immunosuppressed patient showed that In this study, we identified and characterized a novel HBV HBV variants can rapidly accumulate in severe hepatitis mutant in a heart transplantation recipient who died from B and suggest that the novel HNF-1 binding site may 1993, 2 weeks later, the patient died from fulminant hepatitis B.Received September 24, 1996; accepted February 24, 1997. Sera obtained from the donor at the time of transplantation and from Study was...

Complex HBV populations with mutations in core promoter, C gene, and pre-S region are associated with development of cirrhosis in long-term renal transplant recipients

“…Previous studies reporting single cases or reports that focused on subgenomic regions suggested that deletions/insertions in Cp/EnII, deletions in the C gene, and deletions in the pre-S region might be associated with an unfavorable outcome of infection. [5][6][7] These studies were extended here by investigating a large number of patients in comparison with a control group as well as by analyzing complete HBV genomes by PCR and full-length genome cloning. An association between the clinical course and presence of mutations in HBV was studied cross-sectionally and longitudinally.…”

“…The latter have been shown to enhance the pregenomic RNA and core protein levels in vitro. 5,11 This might be a prerequisite for efficient complementation of C gene deletion variants, which fully depend on the supply of functional core protein in trans.…”

“…Several Cp/EnII mutations as described in this study have previously been characterized in cell culture and were found to enhance virus replication by increasing the strength of the pre- genomic promoter. 5,11,16 In most cases, the underlying mechanism is the acquisition of a novel HNF-1 binding site by BCP mutations as listed in Table 4. 5,11 Deletions in the C gene were also shown to confer a growth advantage to wild-type virus 17,18 and to enhance virus replication at the level of pregenome encapsidation or reverse transcription, when the mutant is sufficiently complemented with wild-type core protein.…”

“…5,11,16 In most cases, the underlying mechanism is the acquisition of a novel HNF-1 binding site by BCP mutations as listed in Table 4. 5,11 Deletions in the C gene were also shown to confer a growth advantage to wild-type virus 17,18 and to enhance virus replication at the level of pregenome encapsidation or reverse transcription, when the mutant is sufficiently complemented with wild-type core protein. 18 Core proteins with internal deletions are able to interact with the wild-type core protein and to form mosaic particles.…”

“…Mutations in the core promoter/enhancer II (Cp/EnII) that create a novel hepatocyte nuclear factor (HNF) 1 binding site and deletions in the pre-S region were found in a heart transplant recipient who died from fulminant HBV infection under immunosuppression. 5 A liver transplant recipient died from fibrosing cholestatic hepatitis following the accumulation of HBV with deletions in the pre-S1/2 region. 6 In a previous study, we showed that HBV with deletions in the C gene is significantly associated with development of HBV-related end-stage liver disease (ESLD) and death in renal transplant recipients.…”