Enhancement of Hepatitis B Virus Replication by Its X Protein in Transgenic Mice

Xu, Zhenming; Yen, T. S. Benedict; Wu, Li-Chiu; Madden, Charles R.; Tan, Wenjie; Slagle, Betty L.; Ou, Jing-Hsiung

doi:10.1128/jvi.76.5.2579-2584.2002

Cited by 123 publications

(127 citation statements)

References 40 publications

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“…In transgenic mice, HBx is not essential for HBV replication, but it can enhance viral replication (Reifenberg et al, 2002;Xu et al, 2002). Recently, in vitro experiments suggest that HBx stimulates HBV replication via its transactivation function (Melegari et al, 2005;Tang et al, 2005).…”

Section: Hbxmentioning

confidence: 99%

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

et al. 2006

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As discussed in detail in other chapters of this review, chronic hepatitis B (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Most HCCs complicate the evolution of an active or inactive cirrhosis. However, some tumors occur on livers with minimal histological changes; the prevalence of such cases varies from one geographical region to the other, being much higher in the southern half of Africa (around 40% of HCCs) than in Asia, America and Europe, where at least 90% of HCCs are associated with the cirrhosis. This heterogeneity is probably a reflection of different environmental and genetic factors. This review will summarize the current knowledge on the mechanisms involved in HBVrelated liver carcinogenesis. It will show in particular how viruses can be viewed as tools to discover and dissect new cellular pathways involved in cancer development and emphasize the potential synergistic effects between HBV and hepatitis C virus, as well as between viral infections and other environmental factors, such as alcohol.

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Section: Hbxmentioning

confidence: 99%

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

et al. 2006

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“…The conclusion by Tang et al is clearly different from the direct role of HBx in HBV replication reported by the previous studies. (46,47) Zhang et al reported the involvement of proteasome in the stimulatory role of HBx in HBV transcription and replication. (32) Their experiments demonstrated that HBx-assisted enhancement of HBV transcription and replication is through the proteasomedependent pathway since inhibition of cellular proteasome activities enhanced HBV transcription and replication in an HBx-dependent manner.…”

Section: −10mentioning

confidence: 99%

Molecular functions and biological roles of hepatitis B virus x protein

Tang¹,

Oishi²,

Kaneko³

et al. 2006

Cancer Science

266

244

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Chronic infection of hepatitis B virus (HBV) isH epatitis B virus (HBV) infection is a worldwide health problem and is one of the major causes of hepatocellular carcinoma (HCC) in the world. However, new incidences of HBV infection have been dramatically reduced by several prevention programs. The crucial role of HBV in hepatocarcinogenesis is beyond doubt, however, the mechanism by which HBV causes transformation of hepatocytes remains uncertain.(1-3) Hepatitis B virus X protein (HBx) has long been suspected to play a positive role in hepatocarcinogenesis because HCC incidence has been reported in animals infected with mammalian hepadnaviruses. Among these hepadnaviruses, open reading frame-X (X-ORF) is conserved in the genomes. However, hepatocarcinogenesis has not been found in avian infected with avian hepadnaviruses where X-ORF is absent. In addition to the putative contribution of HBx, other oncogenic mechanisms of the HBV-related hepatocarcinogenesis have also been proposed, such as the integration-dependent scenario of HBV DNA in host genomes, (4) and the inflammation-dependent scenario.(5) Since no higher incidence of HCC has been reported in HBV-expressing transgenic mice, (6) host immunological responses to HBV infection (but not HBV proliferation by itself ) might be primarily contributing to the HBV-related hepatocarcinogenesis. HBx, a small protein of 154 amino acids, is a multifunctional regulator that modulates a variety of host processes through directly or indirectly interacting with virus and host factors. (2,3) In this short review, we briefly summarize the life cycle of HBV, expression of HBx, and the molecular functions of HBx. We then focus on the recent progress on the biological roles of HBx in HBV replication and cellular transformation. Expression and functions of HBx. HBV is a prototype of Hepadnaviridae, hepatotropic small DNA viruses, of which hosts are among limited species of water birds, squirrels and primates. The HBV genome is a 3.2-kb circular, partially double-stranded DNA molecule with four overlapping ORFs, PC-C, PS-S, P, and X-ORFs (Fig. 1). (7) Once HBV infection of hepatocytes occurs, its genome is converted to covalently closed circular (CCC) DNA, which serves as the template for transcription by the host RNA polymerase II, generating the 3.5-, 2.4-, 2.1-, and 0.7-kb transcripts under control of four HBV promoters (Cp, PS1p, Sp, and Xp), respectively (Fig. 1). Two HBV enhancers (Enh I and Enh II) positively regulate transcription of the HBV promoters in combination with the transcription factors that bind these promoters.(7-9) HBV replicates by reverse transcription of the viral pregenomic 3.5-kb RNA (pgRNA) using the HBV polymerase that catalyzes RNA-dependent DNA synthesis and DNA-dependent DNA synthesis. (7,10) The reverse transcription of hepadnaviruses is unique among DNA viruses, and the primer of the reverse transcription is a tyrosine residue of an N-terminal domain of Pol that is distinct from reverse transcription of retroviruses. (10)

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“…The HBV genome contains four open reading frames, encoding the viral envelope protein, the viral core protein, the reverse transcriptase, and the HBV X protein (HBx). The HBx is a 16.5-kDa multifunctional regulator that is essential for virus replication (13,14). To clarify immune mechanisms underlying inhibition of the HBV replication, the relationship between GzmH and HBV clearance was investigated.…”

mentioning

confidence: 99%

Granzyme H of Cytotoxic Lymphocytes Is Required for Clearance of the Hepatitis B Virus through Cleavage of the Hepatitis B Virus X Protein

Tang

Wang

et al. 2012

The Journal of Immunology

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The granule exocytosis pathway of cytotoxic lymphocytes plays critical roles in eradication of intracellular viruses. However, how hepatitis B virus (HBV) is cleared has not been defined. To clarify immune mechanisms underlying inhibition of the HBV replication, the relationship between granzyme H (GzmH) and HBV clearance was investigated. In this study, we found that the granule exocytosis pathway can inhibit HBV replication without induction of cytolysis of the infected cells. GzmH is essential for HBV eradication. The HBx protein (HBx), required for the replication of HBV, is cleaved at Met79 by GzmH. GzmH inhibitor can abolish GzmH- and lymphokine-activated killer cell-mediated HBx degradation and HBV clearance. An HBx-deficient HBV is resistant to GzmH- and lymphokine-activated killer cell-mediated viral clearance. Adoptive transfer of GzmH-overexpressing NK cells into HBV carrier mice facilitates in vivo HBV eradication. Importantly, low GzmH expression in cytotoxic lymphocytes of individuals is susceptible to HBV infection and hepatocellular carcinoma. These results indicate that GzmH might be detected as a potential parameter for diagnosis of HBV infection and hepatocellular carcinoma.

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Enhancement of Hepatitis B Virus Replication by Its X Protein in Transgenic Mice

Cited by 123 publications

References 40 publications

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

Molecular functions and biological roles of hepatitis B virus x protein

Granzyme H of Cytotoxic Lymphocytes Is Required for Clearance of the Hepatitis B Virus through Cleavage of the Hepatitis B Virus X Protein

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