Accumulation and persistence of hepatitis B virus core gene deletion mutants in renal transplant patients are associated with end-stage liver disease

Abstract

Evidence is accumulating that HBV variants may influence In renal transplant recipients, chronic hepatitis B vithe clinical course of hepatitis B. For instance, HBV with rus (HBV) infection often leads to cirrhosis and liver a point mutation in the preC-region (preC-variant), which failure. In this study, we investigated whether or not prevents the expression of the hepatitis B e antigen (HBeAg), in these patients viral variants would emerge despite can be associated with severe liver disease and, in some geoimmunosuppression, and whether they are associated graphic areas, with acute fulminant hepatitis. 1 Recently, it with a specific course of liver disease. In a population was proposed that preC-variants may also be predisposed to of 552 renal transplant recipients hepatitis B 24 surface early graft loss following liver transplantation. 2 In some, but antigen (HBsAg)-positive patients were available for a not all, studies, variants with clustered point mutations or 2-year follow-up. By polymerase chain reaction (PCR) variable long overlapping deletions in the middle of the core and DNA sequencing, HBV genomes with deletions in gene (C-gene) were found in patients with chronic active hepthe middle of the core gene (C-gene) were found in 9 out atitis, but not in patients with mild liver lesions. 3-5 of the 24 patients. Seven of the 9 patients (group I)Some of these and other variants are probably selected by showed either persistent or increasing amounts of these immune-mediated mechanisms, because they were shown to variants; all patients had cirrhosis, and 5 died of endemerge spontaneously in chronic carriers during seroconverstage liver disease. The viral variants emerged at least sion from HBeAg to antibody to HBe (anti-HBe) 6 during in-1 year before liver failure. In 2 out of the 9 patients, terferon therapy 7 and after vaccination. 8 However, other varithe core deletion variants disappeared, and no further ants with deletions or insertions in the C-gene promoter deterioration of the liver function was observed thereafregion seem to have a selective disadvantage when the imter. In the remaining 15 patients (group II) without delemune system is activated. 9 Thus, an effective immune retion mutants detected at any time, only 3 had cirrhosis sponse can trigger both the emergence and the disappearance (P õ .001, group I vs. II), and none died (P õ .001). Beof HBV variants. tween both groups, there were no statistically signifiIt is generally believed that the recognition of a wild-type cant differences in the other relevant variables that or variant HBV by the immune system will result in hepatiwere examined. These results indicate that HBV C-gene tis. The recognition of virtually all viral proteins by the hudeletion mutants can accumulate in long-term immunomoral and cellular immune system 10-11 supports this view, suppressed patients, and that their persistence is associand suggests that an effective immune response is a prerequiated with progressive liver disease. The accumulation site for liver injury. Howe...

Molecular, immunological and clinical properties of mutated hepatitis B viruses

“…This would make the core-deletionmutants dependent on the wildtype virus. The observation that these variants only were found together with the wildtype HBV [13,137,138] and transfection assays [36] could confirm this opinion.…”

“…Core-deletion-mutants could be associated with severe liver diseases like cirrhosis and necroinflammation in immunocompromised [13,15,141] and in immunocompetent patients [137].…”

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 comparison between the study and control groups indicates that the additional occurrence of deletion in the C gene is particularly associated with LC (P Ͻ .0001); this finding is in agreement with a previous study that analyzed only the C gene. 7 In particular, the temporal connection between appearance of the C gene and pre-S deletions and progression of liver disease suggests that the mutants contribute to pathogenesis of LC and ESLD. On the other hand, the data do not exclude that the mutants emerged due to subclinical changes in the liver before LC became clinically apparent and represent only a marker of disease progression.…”

“…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. 7 Whereas the former studies reported just single cases without a control group, the latter was focused on 1 subgenomic region of HBV. Therefore, on the HBV genome level, it is still unclear which type of mutation or which combination of mutations is associated with severe liver disease in immunosuppressed patients and thus might play a role in pathogenesis.…”