The mode of hepatitis B virus DNA integration in chromosomes of human hepatocellular carcinoma.

Nagaya, Tsutomu; Nakamura, Toshio; Tokino, Takashi; Tsurimoto, Toshiki; Imai, Masayuki; Mayumi, Tadanori; Kamino, Kouzin; Yamamura, Ken‐ichi; Matsubara, Kazuo

doi:10.1101/gad.1.8.773

Cited by 194 publications

(131 citation statements)

References 33 publications

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“…Indeed, further analysis of the molecular organization of these recombinant strains disclosed common identical points of recombination: (i) in X-preC (nt 1600-2000); (ii) at the 39 end of the core gene, around nt 2400; (iii) in the Pol-preS1 region, around nt 2800; and (iv) at the end of the preS1 region, around nt 3000. Interestingly, these breakpoints were located in previously described hot-spot recombination and integration regions of the HBV genome (Dejean et al, 1984;Nagaya et al, 1987;Pineau et al, 1998). The so-called cohesive region of the genome, comprising the direct repeat regions (DR1 and DR2), was often involved in this process.…”

Section: Discussionmentioning

confidence: 99%

A novel hepatitis B virus (HBV) subgenotype D (D8) strain, resulting from recombination between genotypes D and E, is circulating in Niger along with HBV/E strains

Chekaraou

Brichler

Mansour

et al. 2010

Journal of General Virology

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Niger is a west African country that is highly endemic for hepatitis B virus (HBV) infection. The seroprevalence for HBV surface antigen (HBsAg) is about 20 %; however, there are no reports on the molecular epidemiology of HBV strains spreading in Niger. In the present study, HBV isolates from the sera of 58 consecutive, asymptomatic, HBsAg-positive blood donors were characterized. Genotype affiliation was determined by amplification, sequencing and phylogenetic analysis of the preS1, polymerase/reverse transcriptase (RT/Pol) and precore (preC)/C regions. The first series of results revealed that different genomic fragments clustered with different genotypes on phylogenetic trees, suggesting recombination events. Twenty-four complete genomic sequences were obtained by amplification and sequencing of seven overlapping regions covering the whole genome, and were studied by extensive phylogenetic analysis. Among them, 20 (83.3 %) were classified unequivocally as genotype E (HBV/E). The remaining four (16.7%) clustered on a distinct branch within HBV/D with strong bootstrap and posterior probability values. Complete molecular characterization of these four strains was achieved by the Simplot program, bootscanning analysis and cloning experiments, and enabled us to identify an HBV/D-E recombinant that formed a new HBV/D subgenotype spreading in Niger, tentatively named D8. Moreover, 20 new complete HBV/E nucleotide sequences were determined that exhibited higher genetic variability than is generally described in Africa. One was found to be a recombinant containing HBV/D sequences in the preS2 and RT/Pol regions. Taken together, these data suggest that, in Niger, genetic variability of HBV strains is still evolving, probably reflecting ancient endemic HBV infection. INTRODUCTIONHepatitis B virus (HBV) infection remains a major public health problem, particularly in Africa, although data for precisely estimating the burden of HBV infection are lacking. It is estimated that 2 billion people worldwide are or have been infected with HBV (WHO: http://www.who. int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf), among whom over 360 million are in a chronic carrier state with a high risk of developing cirrhosis and hepatocellular carcinoma (Ganem & Prince, 2004;Lee et al., 1997;Lok, 2004). About 70-140 million of these carriers live in Africa, and about 250 000 of the 1.3 million HBV-related deaths recorded each year throughout the world occur in Africa (Andernach et al., 2009;Hubschen et al., 2008;Kramvis & Kew, 2007;Kramvis et al., 2002;Mulders et al., 2004). HBV belongs to the family Hepadnaviridae and is characterized by a partially double-stranded circular DNA genome of 3These authors contributed equally to this work.The GenBank/EMBL/DDBJ accession numbers for the sequences determined in this study are FN594748-FN594771.A supplementary list of additional GenBank sequences used in this study is available with the online version of this paper. RESULTS Nucleotide sequences and phylogenetic analysesSeveral nucleot...

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Section: Discussionmentioning

confidence: 99%

A novel hepatitis B virus (HBV) subgenotype D (D8) strain, resulting from recombination between genotypes D and E, is circulating in Niger along with HBV/E strains

Chekaraou

Brichler

Mansour

et al. 2010

Journal of General Virology

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“…The observation that the number and intensity of HBsAg-positive cells in the liver may be preserved despite low-level HBV replication is consistent with this integration. Although integration is believed to be a random event, a high preference for integration has been observed at the DR1 and DR2 sequences on the HBV genome (19), and sequences of the S genes are often present in integrated segments (20). Although integrated sequences cannot provide a template for productive viral replication, HBsAg may be produced (20).…”

Section: Hbsag: Controversiesmentioning

confidence: 99%

“…In HBV infection, viral integration seems to occur in the early stages of infection. Although HBV integration is believed to be a random event, a strong preference for integration occurs at the DR1 and DR2 sequences on the HBV genome (19). Integrated sequences cannot provide a template for productive viral replication as a complete genome is not present (20).…”

Section: Hbsag: Virologymentioning

confidence: 99%

Quantification of hepatitis B surface antigen: a new concept for the management of chronic hepatitis B

Moucari

Marcellin

2011

Liver International

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HBsAg is a very important clinical test that might not only indicate active hepatitis B virus (HBV) infection but might also be used to predict clinical and treatment outcome. Clearance of HBsAg in patients with chronic HBV infection is associated with a much better clinical outcome, although surveillance for early detection of hepatocellular carcinoma (HCC) should continue. HBV DNA quantification is currently used for selecting candidates for therapy, monitoring response to therapy and detecting the emergence of drug resistance. Assays for HBsAg quantification are less expensive than HBV DNA and fully automated with a high throughput capacity. HBsAg titering may be a useful tool to manage patients with chronic HBV, to more clearly define which patients may, and more importantly, may not, benefit from treatment. Baseline and on-treatment HBsAg quantification may help to refine future treatment algorithms for both immune-modulator therapy and nucleos(t)ide analogues. Both HBV markers provide complementary information on the status of HBV infection. However, the relevance of serum HBsAg levels and its use as a reliable replacement for both covalently closed circular DNA and HBV DNA remain unclear.

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“…Integrated HBV sequences in tumor DNA are frequently interrupted between the viral direct repeats DR1 and DR2 (Nagaya et al, 1987), generating 3' truncated versions of the X gene that retain trans-activating capacity (Koshy et al, 1991;Takada et al, 1990;Wei et al, 1995;Wollersheim et al, 1988). Moreover, in HCC patients negative for the HBV surface antigen, accumulation of viral RNAs containing X but not surface or core sequences was evidenced by polymerase chain reaction (PCR) (Paterlini et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

The hepatitis B virus X gene potentiates c-myc-induced liver oncogenesis in transgenic mice

et al. 1997

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The hepatitis B virus X protein (HBx) is thought to be implicated in the development of hepatocellular carcinoma, but its exact function remains controversial. Transgenic mice from PEX7 and AX16 lineages that express HBx in the liver under control of di erent viral regulatory elements develop no liver pathology (Billet et al., 1995). We have crossed these two mouse lineages with WHV/c-myc oncomice in which liver-speci®c expression of c-myc driven by woodchuck hepatitis virus (WHV) regulatory sequences causes liver cancer in all animals. The average tumor latency was shortened by 2 to 3 months in bitransgenic animals from all populations compared with simple c-myc transgenic littermates. At preneoplastic stages, adult bitransgenic mice showed four to ®vefold enhanced expression of the c-myc transgene, increased hepatocyte proliferation and more extensive liver lesions compared with simple WHV/c-myc transgenics. Thus in this model, HBx alone has no direct pathological e ect but it is shown to accelerate tumor development induced by c-myc. The data presented here ®rmly establish the oncogenic potential of HBx, apparently acting as a tumor promoter. This model o ers unique opportunities to investigate the mechanisms by which HBx trans-activates the expression of target genes and deregulates the hepatocyte growth control in vivo.

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The mode of hepatitis B virus DNA integration in chromosomes of human hepatocellular carcinoma.

Cited by 194 publications

References 33 publications

A novel hepatitis B virus (HBV) subgenotype D (D8) strain, resulting from recombination between genotypes D and E, is circulating in Niger along with HBV/E strains

A novel hepatitis B virus (HBV) subgenotype D (D8) strain, resulting from recombination between genotypes D and E, is circulating in Niger along with HBV/E strains

Quantification of hepatitis B surface antigen: a new concept for the management of chronic hepatitis B

The hepatitis B virus X gene potentiates c-myc-induced liver oncogenesis in transgenic mice

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