scholarly journals Hepatitis B Virus X Gene Differentially Modulates Subgenotype F1b and F4 Replication

Viruses ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 655
Author(s):  
María Mercedes Elizalde ◽  
Micaela Speroni ◽  
Rodolfo Héctor Campos ◽  
Diego Martín Flichman
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Regulatory Protein ◽  
Regulatory Elements ◽  
Wild Type ◽  
X Protein ◽  
B Virus ◽  
Common Purpose ◽  
X Gene ◽  
Transcription And Replication

Hepatitis B virus (HBV) is classified into ten genotypes and numerous subgenotypes (sgt). In particular, sgt F1b and sgt F4, native of Latin America, have been associated with differences in clinical and virological characteristics. Hepatitis B virus X protein (HBx) is a multifunctional regulatory protein associated with the modulation of viral transcription and replication. In this work, we analyzed the role of the X gene and the encoded X protein in sgtF1b and sgtF4 replication. Transfection with HBx deficient genomes revealed remarkable differences in the replicative capacity of sgtF1b and sgtF4 mutants. The silencing of HBx increased sgtF1b X(-) transcription and replication by more than 2.5 fold compared to the wild type variant, while it decreased sgtF4 X(-) transcription and replication by more than 3 fold. Trans-complementation of HBx restore sgtF1b and sgtF4 wild type transcription and replication levels. In addition, transfection with chimeric variants, carrying wild type (F1b/XF4 and F4/XF1b) or mutated (F1b/X(-)F4 and F4/X(-)F1b) X gene of one sgt in the backbone of the other sgt, showed that the nucleotide sequence of the X gene, that includes regulatory elements that modulate pgRNA transcription, was responsible for the disparity observed between sgtF1b X(-) and sgtF4 X(-). These results showed that sgtF1b and sgtF4 X gene play a central role in regulating HBV transcription and replication, which eventually lead to a common purpose, to reach wild type replication levels of sgtF1b and sgtF4 viruses.

scholarly journals Role and Functional Domain of Hepatitis B Virus X Protein in Regulating HBV Transcription and Replication in Vitro and in Vivo

Viruses ◽  
2013 ◽  
Vol 5 (5) ◽  
pp. 1261-1271 ◽  
Author(s):  
Dao-Yin Gong ◽  
En-Qiang Chen ◽  
Fei-Jun Huang ◽  
Xiao-Hua Leng ◽  
Xing Cheng ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Functional Domain ◽  
X Protein ◽  
B Virus ◽  
Transcription And Replication

scholarly journals Induction of apoptosis after switch-on of the hepatitis B virus X gene mediated by the Cre/loxP recombination system

1999 ◽  
Vol 80 (12) ◽  
pp. 3257-3265 ◽  
Author(s):  
Yoshizumi Shintani ◽  
Hiroshi Yotsuyanagi ◽  
Kyoji Moriya ◽  
Hajime Fujie ◽  
Takeya Tsutsumi ◽  
...  
Keyword(s):  
Cell Death ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cell Lines ◽  
Liver Cell ◽  
Cre Recombinase ◽  
Wild Type ◽  
Cell Clones ◽  
B Virus ◽  
X Gene

The HBx protein of hepatitis B virus is a multifunctional protein that is implicated in the pathogenesis of hepatocellular carcinoma by regulating gene transcription, causing cell proliferation and, as shown recently, inducing cell death. However, analysis of the effects of HBx in stable cultured cell clones has been hampered because only cell lines that adapted to the effects of HBx were selected during the establishment of cell clones. Here, we describe a system in which transcription of the X gene of hepatitis B virus is switched on by the use of the site-specific Cre recombinase. Two human liver cell lines, HLF and HepG2, were used, the former with a mutant p53 allele and the latter with wild-type p53. The stable cell clones isolated, which carried the X gene in a transcriptionally silent state, were infected with recombinant adenovirus carrying Cre recombinase. Ninety-six hours after adenovirus infection, cell clones that expressed HBx had undergone TUNEL-positive cell death with characteristics of apoptosis. Apoptosis was induced despite concomitant inactivation of the p53 protein as a result of its cytoplasmic translocation by HBx. In contrast, neither the X gene-carrying cells infected with wild-type adenovirus nor various control cells infected with Cre-expressing adenovirus exhibited apoptosis. These results indicate that the expression of HBx protein leads to liver cell apoptosis independently of the p53 pathway. The significance of HBx-induced apoptosis in natural infection is unclear, but it may contribute to the development of hepatitis and serve to spread progeny virus to neighbouring cells while evading the host immune responses.

630 HEPATITIS B VIRUS X PROTEIN AUGMENTS HBV TRANSCRIPTION AND REPLICATION IN VIVO OF MOUSE

2010 ◽  
Vol 52 ◽  
pp. S247
Author(s):  
F.-J. Huang ◽  
H. Tang ◽  
Q.-L. Hou ◽  
E.-Q. Chen ◽  
F.-J. Liu ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
X Protein ◽  
B Virus ◽  
Transcription And Replication

scholarly journals Nuclear Respiratory Factor 1 Plays an Essential Role in Transcriptional Initiation from the Hepatitis B Virus X Gene Promoter

2004 ◽  
Vol 78 (20) ◽  
pp. 10856-10864 ◽  
Author(s):  
Yumiko Tokusumi ◽  
Sharleen Zhou ◽  
Shinako Takada
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Mitochondrial Genes ◽  
Minimal Promoter ◽  
X Protein ◽  
Transcriptional Initiation ◽  
Nuclear Respiratory Factor ◽  
Nuclear Respiratory Factor 1 ◽  
B Virus ◽  
X Gene

ABSTRACT The X gene of hepatitis B virus (HBV) is one of the major factors in HBV-induced hepatocarcinogenesis and is essential for the establishment of productive HBV replication in vivo. Recent studies have shown that the X gene product targets mitochondria and induces calcium flux, thereby activating Ca+-dependent signal transduction pathways. However, regulatory mechanisms of X gene expression have remained unclear. Previous studies had localized a minimal promoter activity to a 21-bp GC-rich sequence located 130 bp upstream of the X protein coding region and showed that there was a cellular protein bound to this DNA. Interestingly, the 21-bp sequence identified as an X gene minimal promoter does not contain any previously identified core promoter elements, such as a TATA box. To better understand the mechanisms of transcriptional initiation of the X gene, we set out to biochemically purify the binding protein(s) for the 21-bp DNA. We report here the identification of the X gene minimal promoter-binding activity as nuclear respiratory factor 1 (NRF1), a previously known transcription factor that activates the majority of nucleus-encoded mitochondrial genes and various housekeeping genes. Primer extension analyses of the X mRNAs show that mutations at the binding site specifically inactivate transcription from this promoter and that a dominant-negative NRF1 mutant and short interfering RNAs inhibit transcription from this promoter. Therefore, NRF1 specifically binds the 21-bp minimal promoter and positively contributes to transcription of the X gene. Simultaneous activation of the X gene and mitochondrial genes by NRF1 may allow the X protein to target mitochondria most efficiently.

scholarly journals Hepatitis B Virus X Protein Acts as a Tumor Promoter in Development of Diethylnitrosamine-Induced Preneoplastic Lesions

2001 ◽  
Vol 75 (8) ◽  
pp. 3851-3858 ◽  
Author(s):  
Charles R. Madden ◽  
Milton J. Finegold ◽  
Betty L. Slagle
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Transgenic Mice ◽  
Dna Lesions ◽  
Tumor Promoter ◽  
Nuclear Antigen ◽  
Wild Type ◽  
Preneoplastic Lesions ◽  
X Protein ◽  
B Virus

ABSTRACT Chronic infection with hepatitis B virus (HBV) is one of the major etiological factors in the development of human hepatocellular carcinoma. Transgenic mice that express the HBV X protein (HBx) have previously been shown to be more sensitive to the effects of hepatocarcinogens. Although the mechanism for this cofactor role remains unknown, the ability of HBx to inhibit DNA repair and to influence cell cycle progression suggests two possible pathways. To investigate these possibilities in vivo, we treated double-transgenic mice that both express HBx (ATX mice) and possess a bacteriophage lambda transgene with the hepatocarcinogen diethylnitrosamine (DEN). Histological examination of liver tissue confirmed that DEN-treated ATX mice developed approximately twice as many focal lesions of basophilic hepatocytes as treated wild-type littermates. Treatment of mice with DEN resulted in a six- to eightfold increase in the mutation frequency (MF), as measured by a functional analysis of the lambda transgene. HBx expression was confirmed by immunoprecipitation and Western blotting and was associated with a modest 23% increase in the MF. Importantly, the extent of hepatocellular proliferation in 14-day-old mice, as measured by the detection of proliferating cell nuclear antigen and by the incorporation of 5-bromo-2′-deoxyuridine, was determined to be approximately twofold higher in ATX livers than in wild-type livers. These results are consistent with a model in which HBx expression contributes to the development of DEN-mediated carcinogenesis by promoting the proliferation of altered hepatocytes rather than by directly interfering with the repair of DNA lesions.

Precore/Core Promoter Mutant Hepatitis B Virus Produces More Severe Histologic Liver Disease than Wild Type Hepatitis B Virus

2007 ◽  
Vol 1 (1) ◽  
pp. 41-46 ◽  
Author(s):  
Mamun-Al-Mahtab ◽  
Salimur Rahman ◽  
Mobin Khan ◽  
Ayub Mamun ◽  
Kamal
Keyword(s):  
Liver Disease ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Core Promoter ◽  
Wild Type ◽  
B Virus ◽  
Promoter Mutant
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