1. |
- Kidd-Ljunggren, Karin, et al.
(författare)
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Genetic variability in hepatitis B viruses.
- 2002
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Ingår i: Journal of General Virology. - 1465-2099. ; 83:Pt 6, s. 1267-1280
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Forskningsöversikt (refereegranskat)abstract
- In 1988, it was reported that the full nucleotide sequences of 18 hepatitis B virus (HBV) strains clustered into four genetic groups (A to D) with more than 8% divergence between the groups. This classification of strains in terms of genome sequence has since proven to be an important tool in the understanding of HBV epidemiology and evolution and has been expanded to include three more genotypes. In parallel with the HBV genotypes described in humans, HBV strains isolated from different primates and hepadnaviruses found in woodchucks, ground squirrels, ducks and herons have been studied. Sequence differences between HBV genotypes can lead to structural differences at the level of the pregenome and can also lead to dramatic differences at the translational level when specific and commonly occurring mutations occur. There is increasing evidence that the clinical picture, the response to treatment and the long-term prognosis may differ depending on which genotype has infected the patient. The consideration of traditional serological patterns in a patient must therefore take the genotype of the infecting strain into account. Nucleotide variability between HBV strains has been used in several studies to trace routes of transmission and, since it is becoming increasingly clear that the differences between HBV genotypes are important, the need for reliable and easy methods of differentiating HBV genotypes has arisen. This review summarizes the knowledge of HBV genotypes with regard to their genetic, structural and clinically significant differences and their origin and evolution in the context of the hepadnaviruses in general.
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2. |
- Bläckberg, Jonas, et al.
(författare)
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Genotypic differences in the hepatitis B virus core promoter and precore sequences during seroconversion from HBeAg to anti-HBe
- 2000
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Ingår i: Journal of Medical Virology. - 1096-9071. ; 60:2, s. 107-112
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Tidskriftsartikel (refereegranskat)abstract
- Hepatitis B virus (HBV) strains from anti-HBe positive patients often show specific mutations in the precore gene, the core promoter region, or both. The dynamics of seroconversion in relation to the appearance of these mutations has not been studied and compared between defined HBV genotypes. Samples from patients followed during seroconversion from HBeAg to anti-HBe were amplified by polymerase chain reaction (PCR), sequenced and genotyped. Among 16 sets of samples, 6 belonged to genotype A, 6 to genotype D, 2 to genotype B, 1 to genotype C, and 1 to genotype E. Whereas strains from genotypes B, C and E showed changes in the core promoter, precore codon 28 or both, genotype A and D strains displayed a different pattern. In 4 of 6 anti-HBe positive samples from genotype A, the precore had a wild-type sequence while the core promoter sequence showed a specific TGA mutation. In another genotype A strain a precore stop mutation was preceded by a mutation in codon 15, thus conserving base-pairing at the pregenomic RNA level in this region. In contrast, all genotype D strains showed wild-type sequences in both the core promoter and precore codon 28 in pre- and post-seroconversion samples. Thus, in 8 patients with a mean follow-up time of 17 months, wild-type sequences in both the core promoter and precore codon 28 were found after seroconversion to anti-HBe. This study also confirmed, for genotype D, that HBeAg seroconversion often occurs earlier than genomic conversion.
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3. |
- Bläckberg, Jonas, et al.
(författare)
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Long-term outcome of acute hepatitis B and C in an outbreak of hepatitis in 1969-72
- 2000
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Ingår i: European Journal of Clinical Microbiology & Infectious Diseases. - : Springer Science and Business Media LLC. - 1435-4373 .- 0934-9723. ; 19:1, s. 21-26
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to investigate the epidemiology, etiology, and long-term outcome of an extended outbreak of acute hepatitis that occurred in an area of Sweden between 1969 and 1972. The outbreak was analyzed retrospectively by retesting stored frozen serum samples for the presence of hepatitis A, B and C markers. The results were compared with the diagnoses that had been determined during the outbreak. Of 180 patients, 29 (16%) had acute hepatitis A, 126 (70%) had acute hepatitis B, and eight (4.4%) had acute hepatitis C. The Australia antigen test used during the outbreak had failed to identify 21 patients with acute hepatitis B virus infection. Genotyping of the hepatitis B virus strains showed that genotype D was the most prevalent, irrespective of the transmission route. An attempt was made to follow up patients with unresolved hepatitis B virus infection, 25-27 years after the acute infection. None of the 100 patients with acute hepatitis B infection who were traced had become chronic carriers. In ten patients with hepatitis C virus infection, the follow-up showed considerable variation in the outcome, ranging from spontaneous resolution to death through liver cirrhosis. Intravenous drug users had a high prevalence of hepatitis C virus infection, with 52% testing positive for hepatitis C antibodies.
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4. |
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5. |
- Bläckberg, Jonas, et al.
(författare)
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Occult hepatitis B virus after acute self-limited infection persisting for 30 years without sequence variation
- 2000
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Ingår i: Journal of Hepatology. - 0168-8278. ; 33:6, s. 992-997
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND/AIMS: After acute self-limited hepatitis B virus (HBV) infection, serological loss of viral antigens and appearance of anti-HBs is generally believed to signify viral clearance. Latent and occult HBV infection appearing decades after self-limited hepatitis B has not been reported, nor has the evolutionary rate of HBV DNA over the same observation period. METHODS: DNA from serum and leukocytes from 16 patients with acute self-limited hepatitis B 30 years earlier was tested by polymerase chain reaction and positive samples were sequenced. Liver tissue from four patients was also tested. Additionally, another 10 HBV strains isolated from acute HBV cases in 1969-72 were compared to 11 strains isolated from acute cases in 1998-99 in the same community. RESULTS: HBV DNA was detected in liver from two patients, but not in serum or leukocytes. The HBV strains detected in liver showed complete homology, in the sequences analyzed, to the strains originally infecting these patients. Ten strains from 1998-99 were identical in pre-S and core promoter/precore regions to strains from the same community isolated 30 years earlier. CONCLUSIONS: HBV can persist as an occult infection three decades after acute, apparently self-limited hepatitis B, and both the mutation and evolutionary rates of HBV DNA are low.
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6. |
- Flodell, Sara, et al.
(författare)
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Structure elucidation of the hepatitis B virus encapsidation signal by NMR on selectively labeled RNAs.
- 2002
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Ingår i: Journal of Biomolecular Structure and Dynamics. - 0739-1102 .- 1538-0254. ; 19:4, s. 627-636
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Hepatitis B virus (HBV) HBV is DNA virus with a unique replication strategy, which involves reverse transcription of its pregenomic RNA. Essential for this reverse transcription are the 5'- and 3'-ends of its pregenomic RNA (5'-RT-RNA and 3'-RT-RNA, respectively) which form conserved bulged stem-loop structures. The 5'-RT-RNA consists of a 67 nucleotide bulged stem-loop structure, epsilon, which constitutes the signal for encapsidation of the pregenomic RNA and subsequent reverse transcription. The reverse transcriptase (RT) initially binds to the completely conserved apical loop of epsilon and a 4-nucleotide primer is synthesized from the adjacent 6-nucleotide bulge. Structural studies of epsilon can provide important parameters required for the design of RNA targeted anti- viral drugs directed against Hepatitis B virus. NMR studies of large RNA systems (> ca. 50 nucleotides) require novel approaches, e.g., different labeling schemes and reduction of the system into separate structural building blocks. Recently, a new method of synthesizing (13)C/(15)N/(2)H labeled nucleotides has been developed based on converting specifically labeled glucose and bases into nucleotides by using enzymes from the pentose phosphate pathway and nucleotide and salvage pathways. These NTPs give a large freedom in designing different labeling patterns in in vitro synthesized RNAs under study for NMR. This opens up the way for NMR studies of RNAs that are considerably above the present size limit (up to 150 nucleotides). Here this new technique is applied for structural studies on 27, 36 and 61 nucleotides long RNA fragments, mimicking different regions of epsilon.
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7. |
- Flodell, Sara, et al.
(författare)
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The apical stem-loop of the hepatitis B virus encapsidation signal folds into a stable tri-loop with two underlying pyrimidine bulges.
- 2002
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 30:21, s. 4803-4811
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Tidskriftsartikel (refereegranskat)abstract
- Reverse transcription of hepatitis B virus (HBV) pregenomic RNA is essential for virus replication. In the first step of this process, HBV reverse transcriptase binds to the highly conserved encapsidation signal, epsilon (epsilon), situated near the 5' end of the pregenome. epsilon has been predicted to form a bulged stem-loop with the apical stem capped by a hexa- loop. After the initial binding to this apical stem- loop, the reverse transcriptase synthesizes a 4 nt primer using the bulge as a template. Here we present mutational and structural data from NMR on the apical stem-loop of epsilon. Application of new isotope-labeling techniques (13C/15N/2H-U-labeling) allowed resolution of many resonance overlaps and an extensive structural data set could be derived. The NMR data show that, instead of the predicted hexa-loop, the apical stem is capped by a stable UGU tri-loop closed by a C-G base pair, followed by a bulged out C. The apical stem contains therefore two unpaired pyrimidines (C1882 and U1889), rather than one as was predicted, spaced by 6 nt. C1882, the 3' neighbour to the G of the loop-closing C-G base pair, is completely bulged out, while U1889 is at least partially intercalated into the stem. Analysis of 205 of our own HBV sequences and 1026 strains from the literature, covering all genotypes, reveals a high degree of conservation of epsilon. In particular, the residues essential for this fold are either totally conserved or show rare non-disruptive mutations. These data strongly indicate that this fold is essential for recognition by the reverse transcriptase.
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8. |
- Kidd-Ljunggren, Karin, et al.
(författare)
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Clinical and serological variation between patients infected with different Hepatitis B virus genotypes.
- 2004
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Ingår i: Journal of Clinical Microbiology. - 1098-660X. ; 42:12, s. 5837-5841
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Tidskriftsartikel (refereegranskat)abstract
- Hepatitis B virus (HBV) has eight genotypes which have distinct geographical distributions. Studies comparing differences in the clinical outcomes of infections caused by strains with genotype-related variations in the HBV genome have largely compared genotypes B and C and genotypes A and D but not all four genotypes. The present study included 196 HBV-infected patients attending an infectious diseases outpatient clinic in Sweden. The age and geographic origin, liver function, HBeAg and anti-HBe status, and the presence or absence of HBV DNA were analyzed for each patient. HBV DNA was detected in 144 patients, and the HBV genotype and the core promoter and precore sequences were determined for the isolates from 101 of these patients. Among the patients who might be considered most likely to be nonviremic, namely, anti-HBe-positive HBV carriers with normal alanine aminotransferase (ALT) levels, 65% had detectable HBV DNA and were thus viremic. Among the viremic patients, HBeAg-positive patients were more likely to have elevated ALT levels than anti-HBe-positive patients. HBV genotypes A to F were represented in the study, and their distributions coincided accurately with the origin of the patient. A significantly higher number of genotype D-infected patients were anti-HBe positive and had elevated ALT levels (42% of genotype D-infected patients but 0% of patients infected with genotypes B and C). Genotype D strains with mutations in the core promoter and precore regions were significantly correlated with elevated ALT levels in the patients. The differences were not age related. Therefore, in this large-scale cross-sectional study, genotype D appears to be associated with more active disease.
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10. |
- Widell, Anders, et al.
(författare)
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Hepatocellular carcinoma in Sweden: its association with viral hepatitis, especially with hepatitis C viral genotypes
- 2000
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Ingår i: Scandinavian Journal of Infectious Diseases. - : Informa UK Limited. - 1651-1980 .- 0036-5548. ; 32:2, s. 147-152
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Tidskriftsartikel (refereegranskat)abstract
- Viral markers of chronic hepatitis were tested for in 95 frozen serum samples from 299 patients from Malmo, Sweden, with hepatocellular carcinoma (HCC), diagnosed between 1977 and 1994. Hepatitis B analysis included anti-HBc, HBsAg and, if anti-HBc positive, HBV DNA. Hepatitis C infection analysis included anti-HCV screening, RIBA, HCV RNA and HCV genotyping. HCV genotyping was also carried out in 9 HCV-viraemic HCC-patients from Gothenburg. HCV genotype distribution in HCC cases was compared with Swedish HCV-infected blood donors. Among the 95 patients from Malmo, 28 (29%) had anti-HBc, but only 5 (5%) were chronic HBV carriers, compared with 16 (17%) with chronic hepatitis C (p = 0.021). HCV-related HCC was more common among immigrants (8/16 vs. 8/79; p < 0.001). Genotyping of 25 HCV-infected cases showed genotype 1a in 6 (24%), genotype 1b in 13 (52%), genotype 2b in 4 (16%), and genotype 3a in 2 (8.0%) patients. Genotype 1b was more common among HCC patients than among blood donors (p < 0.001), but 8 of 13 genotype 1b-infected patients were from countries where genotype 1b is predominant. Among native Swedes there was no difference between the HCV genotypes infecting blood donors and those found in HCC patients.
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