The hepatitis B virus X gene: analysis of functional domain variation and gene phylogeny using multiple sequences

Kidd‐Ljunggren, Karin; Öberg, Monica; Kidd, Alistair H.

doi:10.1099/0022-1317-76-9-2119

Cited by 82 publications

(74 citation statements)

References 39 publications

(33 reference statements)

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“…The main focus of the previous studies was on the mutations potentially associated with the development of fulminant hepatitis or HCC and on those located in the areas of the X gene encoding the basic core promoter and the core upstream regulatory sequences. Overall, the HBV X gene appears to be well conserved during chronic hepatitis B, and conservation of the X protein seems to be essential for the virus' ability to actively replicate (2,19). On the other hand, mutations in the HBV X gene sequence have been documented in HCC (5,20).…”

Section: Discussionmentioning

confidence: 99%

Repeated Passage of Wild-Type Woodchuck Hepatitis Virus in Lymphoid Cells Does Not Generate Cell Type-Specific Variants or Alter Virus Infectivity

Mulrooney‐Cousins¹,

Michalak

2008

J Virol

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Woodchuck hepatitis virus (WHV), which is closely related to human hepatitis B virus, infects the liver but also invariably establishes persistent infection in the lymphatic system. Although the dose of invading virus appears to be the main factor in determining whether WHV infection is restricted to the lymphatic system or also engages the liver, the nature of WHV lymphotropism remains unclear and a role for a specific lymphotropic variant was not excluded. The availability of woodchuck lymphocyte and hepatocyte cultures susceptible to WHV infection allows investigation of this issue in vitro. We hypothesized that repeated passage of wild-type WHV in lymphoid cells should lead to enrichment of a lymphotropic virus variant, if in fact such a variant exists. For this purpose, wild-type WHV with a homogeneous sequence was used as the inoculum, while lymphoid cells from a single healthy woodchuck donor and a normal woodchuck WCM-260 hepatocyte line served as infection targets. The serial passage of the wild-type virus repeated up to 13 times for both cell types did not lead to the emergence of cell type-specific WHV variants, as revealed by sequence analysis of the virus envelope and the core and X gene sequences. Moreover, the virus passaged in both cell types remained infectious for naive woodchucks, produced infection profiles that depended upon virus dose but not on virus cellular origin, and retained its initial DNA sequence. These results imply that WHV lymphotropism is a natural propensity of the wild-type virus and is not a consequence of infection with a viral variant.Accumulated evidence indicates that hepadnaviruses are capable of replication not only in hepatocytes but also in cells of the immune system. In regard to symptomatic, chronic hepatitis B virus (HBV) infection, which is characterized by the continuous presence of HBV surface antigen (HBsAg) in serum and protracted liver necroinflammation, long-term persistence of virus has been shown in both the liver and the lymphatic system (6,21,26,35,42,43,45). However, liver and lymphoid cells have also been found to be the sites of HBV genome carriage in serum HBsAg-negative patients in whom acute hepatitis (AH) had apparently resolved completely when sensitive PCR-based assays were applied to detect the virus genome (3,4,30,37,40,46). This occult form of HBV infection might be a source of infectious virus available for transmission to healthy individuals through blood or organ donations (1,12,21,24,27), as well as a potential cause of diseases of seemingly unknown etiology engaging the liver and the lymphatic system. In this regard, retrospective studies of hepatocellular carcinoma (HCC) of previously undetermined etiology showed low levels of HBV genomes in 63.5% of liver tissue samples tested (38). In some of those cases, integration of viral DNA into the host's genome was detected. This implies that trace amounts of HBV, identifiable by molecular assays of a sensitivity greater than those currently used in clinical laboratories, may retain pathogeni...

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Section: Discussionmentioning

confidence: 99%

Repeated Passage of Wild-Type Woodchuck Hepatitis Virus in Lymphoid Cells Does Not Generate Cell Type-Specific Variants or Alter Virus Infectivity

Mulrooney‐Cousins¹,

Michalak

2008

J Virol

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“…Mutations at positions 1809 and 1812 have previously been reported to occur only occasionally: in a Philippino man, 32 in 1 out of 29 HBV strains from 14 different countries, 37 and in chronic hepatitis patients after orthotopic liver transplantation. 40 In the present study these mutations were found in 80% of all sequences.…”

Section: Discussionmentioning

confidence: 99%

High prevalence of 1762T 1764A mutations in the basic core promoter of hepatitis B virus isolated from black africans with hepatocellular carcinoma compared with asymptomatic carriers

1999

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The purpose of this study was to identify mutations in the basic core promoter and enhancer II region of the hepatitis B virus (HBV) that might cause the HBV e antigen (HBeAg)-negative phenotype and contribute to hepatocarcinogenesis in black African carriers of the virus. The basic core promoter/enhancer II overlaps with the X gene. HBV DNA from serum of 47 asymptomatic carriers and 50 patients with hepatocellular carcinoma and from 28 tumor and 10 nontumor liver tissues was amplified and sequenced directly. That part of the enhancer II region not overlapping the basic core promoter was completely conserved in all samples. Missense mutations at nucleotides 1809 and 1812 in the basic core promoter were found in 80% of all sequences and may represent wild-type sequence in Southern African isolates. Nucleotide and amino acid divergences were higher in the basic core promoter of hepatocellular carcinoma patients when compared with asymptomatic carriers (P F .0001). This applied particularly to the paired 1762 adenine to thymine (1762 T ) and 1764 guanine to adenine (1764 A ) missense mutations, the prevalence of which was 66% in patients with hepatocellular carcinoma compared with 11% in asymptomatic carriers (P F .0001). Black Africans who are symptomless carriers of the hepatitis B virus (HBV) usually seroconvert from HBV e antigen (HBeAg) positivity to negativity after a relatively short time. 1 The carrier state is established in the first few years of life, 2 and by early adulthood between 1% and 14% only of black carriers remain HBeAg positive compared with 40% or more among ethnic Chinese, another population in which the virus is endemic. 1-4 Why black African carriers seroconvert earlier is not known. Nucleotide sequencing of the precore region of HBV isolates from a number of countries has shown the 1896 stop codon mutation to be a frequent cause of the HBeAgnegative phenotype, 5,6 with other nonsense or frame-shift mutations accounting for a small proportion (reviewed in Miyakawa et al. 7 ). However, these mutations are seldom present in black African carriers in Southern Africa 8,9 and our focus has shifted to the X open reading frame.The X open reading frame encodes the X protein that has transactivating activity (reviewed in Koike and Takada 10 ) and contains the basic core promoter (BCP)/enhancer II complex. The BCP, mapping between nucleotides 1742 and 1849, controls the transcription of both precore messenger RNA (mRNA), which codes for the protein that is the precursor of the e antigen, and pregenomic RNA (pgRNA), which controls HBV replication. 11 A pair of mutations in the BCP that is associated with a reduced level of HBeAg expression was first described in Japanese patients [12][13][14] : an adenine (A) to thymine (T) transversion at position 1762 together with a guanine (G) to A transition at 1764 in the second AT-rich region of the BCP are often present in patients with chronic hepatitis B [15][16][17][18][19][20] and fulminant hepatitis B, [14][15][16][21][22][23] and less often in asymptoma...

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“…This mutation converts codon 28 of the precore sequence to a termination codon and thus prevents HBeAg from being expressed. Other mutations which can also cause the HBeAg − phenotype include other nonsense and frameshift mutations in the precore region (Carmen et al, 1989 ;Hawkins et al, 1994 ;Raimondo et al, 1994 ;Tong et al, 1990) and\or various mutations in the basal core promoter (BCP) (Kaneko et al, 1995 ;Kidd-Ljunggren et al, 1995 ;Kurosaki et al, 1996 ;Laskus et al, 1995 ;Okamoto et al, 1994 ;Sato et al, 1995 ;Takahashi et al, 1995), which has been mapped between nt 1744 to 1804 (Yuh et al, 1992 ;Zhang & McLachlan, 1994). The HBeAg − mutants often become the dominant virus quasispecies in the virus population present in HBV-infected individuals after the appearance of anti-HBeAg (Carmen et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

“…These ' HBeAg-suppressive ' mutants contain a double-mutation of nt 1762 from A T and nt 1764 from G A in the BCP and are frequently the predominant HBV quasispecies observed in patients with chronic hepatitis symptoms (Kaneko et al, 1995 ;Kidd-Ljunggren et al, 1995 ;Kurosaki et al, 1996 ;Laskus et al, 1995 ;Okamoto et al, 1994 ;Sato et al, 1995 ;Takahashi et al, 1995). Our recent studies revealed that this double mutation reduced the level of transcription of the precore RNA and hence the level of expression of HBeAg, yet had no effect on the expression of other HBV transcripts (Buckwold et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Effects of a frequent double-nucleotide basal core promoter mutation and its putative single-nucleotide precursor mutations on hepatitis B virus gene expression and replication.

Buckwold

Yen

et al. 1997

Journal of General Virology

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The basal core promoter (BCP) of hepatitis B virus (HBV) directs the transcription of both precore RNA and core RNA which code for e antigen (HBeAg) and core antigen, respectively. A double mutation in the BCP which converts nucleotide (nt) 1762 from A to T and nt 1764 from G to A is frequently observed in patients with chronic hepatitis B. We recently demonstrated that this double mutation prevented the binding of a liver-enriched factor (LEF) to the BCP, suppressed only precore RNA transcription (and hence HBeAg expression), and enhanced progeny virus production. In order to understand the mechanism for the selection of this frequent double mutation, we have extended our previous studies to further characterize LEF and to compare the effects of this double-nucleotide mutation (M1) with each single-nucleotide mutation at nt 1762 (M2) and nt 1764 (M3). Our results indicate that

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The hepatitis B virus X gene: analysis of functional domain variation and gene phylogeny using multiple sequences

Cited by 82 publications

References 39 publications

Repeated Passage of Wild-Type Woodchuck Hepatitis Virus in Lymphoid Cells Does Not Generate Cell Type-Specific Variants or Alter Virus Infectivity

Repeated Passage of Wild-Type Woodchuck Hepatitis Virus in Lymphoid Cells Does Not Generate Cell Type-Specific Variants or Alter Virus Infectivity

High prevalence of 1762T 1764A mutations in the basic core promoter of hepatitis B virus isolated from black africans with hepatocellular carcinoma compared with asymptomatic carriers

Effects of a frequent double-nucleotide basal core promoter mutation and its putative single-nucleotide precursor mutations on hepatitis B virus gene expression and replication.

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