Monoclonal antibodies raised to purified woodchuck hepatitis virus core antigen particles demonstrate X antigen reactivity

Feitelson, Mark A.; Clayton, Marcia M.; Phimister, Bette

doi:10.1016/0042-6822(90)90491-9

Cited by 14 publications

(6 citation statements)

References 28 publications

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“…We also considered that a function of HBx may be needed for optimal capsid stability. There is an unconfirmed report of HBx "reactivity" in viral cores (4). However, HBx could indirectly affect capsid stability.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of Hepatitis B Virus Replication by the Regulatory X Protein In Vitro and In Vivo

Keasler

Hodgson

Madden

et al. 2007

J Virol

158

177

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The 3.2-kb hepatitis B virus (HBV) genome encodes a single regulatory protein termed HBx. While multiple functions have been identified for HBx in cell culture, its role in virus replication remains undefined. In the present study, we combined an HBV plasmid-based replication assay with the hydrodynamic tail vein injection model to investigate the function(s) of HBx in vivo. Using a greater-than-unit-length HBV plasmid DNA construct (payw1.2) and a similar construct with a stop codon at position 7 of the HBx open reading frame (payw1.2*7), we showed that HBV replication in transfected HepG2 cells was reduced 65% in the absence of HBx. These plasmids were next introduced into the livers of outbred ICR mice via hydrodynamic tail vein injection. At the peak of virus replication, at 4 days postinjection, intrahepatic markers of HBV replication were reduced 72% to 83% in mice injected with HBx-deficient payw1.2*7 compared to those measured in mice receiving wild-type payw1.2. A second plasmid encoding HBx was able to restore virus replication from payw1.2*7 to wild-type levels. Finally, viremia was monitored over the course of acute virus replication, and at 4 days postinjection, it was reduced by nearly 2 logs in the absence of HBx. These studies establish that the role for HBx in virus replication previously shown in transfected HepG2 cells is also apparent in the mouse liver within the context of acute hepatitis. Importantly, the function of HBx can now be studied in an in vivo setting that more closely approximates the cellular environment for HBV replication.Hepatitis B virus (HBV) infection is a major health problem worldwide, with more than 350 million chronically infected individuals who are at risk for developing severe liver disease, including hepatocellular carcinoma (12). The 3.2-kb HBV genome encodes a single regulatory protein termed HBx, but progress towards understanding the role of HBx in virus replication has been hindered by the lack of either a cell culture system or a convenient small animal model. Although initial studies suggested that HBx was not required for virus replication in cell culture (2), experiments with the highly related woodchuck hepatitis virus (WHV) system indicate that the WHV X protein (WHx) is required for virus replication in vivo (23). Other studies have demonstrated that WHVs carrying mutant WHx grow with attenuated kinetics in vivo, depending on the particular mutation (17,22).While many functions have been ascribed to HBx (reviewed in reference 5), most studies have been performed in cell culture and under conditions in which HBx is not required for virus replication. Two recent advances provide new approaches to investigate a role for HBx in the context of virus replication in vivo. The first is a plasmid-based replication assay that utilizes a greater-than-unit-length HBV genome of the ayw subtype (payw1.2) (15) and an identical plasmid containing a stop codon affecting HBx amino acid position 7 (payw1.2*7) (10). These plasmids were used to demonstrate that capsidassoc...

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Section: Discussionmentioning

confidence: 99%

Enhancement of Hepatitis B Virus Replication by the Regulatory X Protein In Vitro and In Vivo

Keasler

Hodgson

Madden

et al. 2007

J Virol

158

177

View full text Add to dashboard Cite

show abstract

“…However, experimental infection with a mutant of WHV that does not encode woodchuck hepatitis x (WHx) antigen yielded no carrier state and no CLD [57,58], suggesting that trans-activation of virus gene expression and replication is central to the establishment of the carrier state. Among infected woodchucks, there was co-staining between WHV core antigen (where virus replication takes place) and WHx [59,60], while in human infection, HBx often co-existed with HBe in serum [61] and replication complexes (i.e., with HBcAg) in the liver [62]. Thus, HBx expression is associated with virus replication.…”

Section: Contribution Of Hbx To Pathogenesis Of Cld By Regulation Of mentioning

confidence: 99%

Pathogenesis of Hepatitis B Virus Associated Chronic Liver Disease

Feitelson¹

2018

Liver Cancer

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Hepatitis B virus (HBV) infection is associated with chronic liver diseases (CLD), which progress from hepatitis to fibrosis, cirrhosis, and finally hepatocellular carcinoma (HCC) over 30-50 years. The pathogenesis of CLD is immune mediated, which is characterized by persistent immune responses against virus infected hepatocytes. During bouts of CLD, the virus gene encoding the hepatitis B x antigen (HBx) is increasingly found integrated at multiple sites within the human genome. Many of these integrated templates express HBx, which is a trans-regulatory protein that supports virus gene expression and replication on one hand, but also alters patterns of gene expression in the infected cell. HBx alters gene expression by constitutively activating signal transduction pathways in the cytoplasm and promoting epigenetic mediated changes in the expression of cellular genes. In doing so, HBx contributes to the persistence of virus infected cells and to the pathogenesis of CLD by triggering multiple hallmarks which are characteristic of cancer.

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“…CAT activity was present in HepG2CAT, but not in HepG2X cells (Figure 1a). For the detection of HBxAg, lysates prepared from 5610 6 cells were immunoprecipitated with monoclonal anti-x (Feitelson and Clayton, 1990;Feitelson et al, 1990bFeitelson et al, , 1993. The immunoprecipitates were then analysed by SDS ± PAGE and Western blotting using a mixture of X peptide antisera, as described (Feitelson and Clayton, 1990;Feitelson et al, 1990aFeitelson et al, , 1993.…”

Section: Establishment Of Hepg2x and Hepg2cat Cellsmentioning

confidence: 99%

The translation initiation factor, hu-Sui1 may be a target of hepatitis B X antigen in hepatocarcinogenesis

et al. 1999

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The role of hepatitis B virus X antigen in the development of hepatocellular carcinoma was explored by stably transfecting HepG2 cells with an X antigen expression vector, and identifying the dierences in gene expression that distinguish X positive from X negative cells by subtractive PCR. One dierentially expressed gene, the human homolog of sui1 (hu-sui1), encodes a translation initiation factor whose expression was suppressed by X antigen in HepG2 cells. Hu-Sui1 was also expressed in nontumor liver but not in tumor cells from patients with hepatocellular carcinoma. Introduction of hu-sui1 into HepG2 cells inhibited cell growth in culture, in soft agar, and partially inhibited tumor formation in nude mice. Hence, the suppression of husui1 by X antigen may result in the abrogation of negative growth regulation and contribute to the development of hepatocellular carcinoma.

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Monoclonal antibodies raised to purified woodchuck hepatitis virus core antigen particles demonstrate X antigen reactivity

Cited by 14 publications

References 28 publications

Enhancement of Hepatitis B Virus Replication by the Regulatory X Protein In Vitro and In Vivo

Enhancement of Hepatitis B Virus Replication by the Regulatory X Protein In Vitro and In Vivo

Pathogenesis of Hepatitis B Virus Associated Chronic Liver Disease

The translation initiation factor, hu-Sui1 may be a target of hepatitis B X antigen in hepatocarcinogenesis

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