Cytoplasmic (but not Nuclear) Hepatitis B Virus (HBV) Core Antigen Reflects HBV DNA Synthesis at the Level of the Infected Hepatocyte

Gowans, Eric J.; Burrell, Christopher J.; Jilbert, Allison R.; Marmion, B. P.

doi:10.1159/000149646

Cited by 46 publications

(32 citation statements)

References 8 publications

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“…Considerable evidence exists that is consistent with this model. In humans (7,17), woodchucks (33), and, as illustrated here, chimpanzees (Fig. 8), a common feature of long-term infections is the emergence of large numbers of hepatocytes that no longer support hepadnavirus replication and antigen expression.…”

Section: Discussionmentioning

confidence: 92%

Detection of Clonally Expanded Hepatocytes in Chimpanzees with Chronic Hepatitis B Virus Infection

Mason

Low

et al. 2009

J Virol

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During a hepadnavirus infection, viral DNA integrates at a low rate into random sites in the host DNA, producing unique virus-cell junctions detectable by inverse nested PCR (invPCR). These junctions serve as genetic markers of individual hepatocytes, providing a means to detect their subsequent proliferation into clones of two or more hepatocytes. A previous study suggested that the livers of 2.4-year-old woodchucks (Marmota monax) chronically infected with woodchuck hepatitis virus contained at least 100,000 clones of >1,000 hepatocytes (W. S. Mason, A. R. Jilbert, and J. Summers, Proc. Natl. Acad. Sci. USA 102:1139-1144, 2005). However, possible correlations between sites of viral-DNA integration and clonal expansion could not be explored because the woodchuck genome has not yet been sequenced. In order to further investigate this issue, we looked for similar clonal expansion of hepatocytes in the livers of chimpanzees chronically infected with hepatitis B virus (HBV). Liver samples for invPCR were collected from eight chimpanzees chronically infected with HBV for at least 20 years. Fifty clones ranging in size from ϳ35 to 10,000 hepatocytes were detected using invPCR in 32 liver biopsy fragments (ϳ1 mg) containing, in total, ϳ3 ؋ 10 7 liver cells. Based on searching the analogous human genome, integration sites were found on all chromosomes except Y, ϳ30% in known or predicted genes. However, no obvious association between the extent of clonal expansion and the integration site was apparent. This suggests that the integration site per se is not responsible for the outgrowth of large clones of hepatocytes.There are approximately 10 12 hepatocytes in the human liver, virtually all of which can be infected during a hepatitis B virus (HBV) infection. Chronic infection leads to the development of hepatocellular carcinomas (HCC) in ϳ25% of patients, with tumors typically emerging after several decades. The tumors are clonal and usually contain integrated HBV DNA that was acquired at an early step in transformation, prior to tumor outgrowth. The tumors themselves typically do not support virus replication and do not contain covalently closed circular DNA (cccDNA), the virus transcriptional template. The fact that the tumors typically contain integrated HBV DNA suggests that they arise through mutation of mature hepatocytes and not from hepatic stem cells or hepatobiliary progenitor cells (37,44,62). Though contrary reports have appeared (3, 21), hepatocytes are currently the only liver cell type unambiguously established to be susceptible to HBV infection in most individuals.With a few exceptions, the virus integration sites found in HCC samples from different patients have not provided insights into the mechanisms of carcinogenesis (8, 9, 53). Aside from showing a possible preference for transcriptionally active regions (36), the sites of HBV integration have appeared somewhat random in location and, by inference, not directly related to cellular transformation. Thus, it has been hypothesized that hepatocyte trans...

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Section: Discussionmentioning

confidence: 92%

Detection of Clonally Expanded Hepatocytes in Chimpanzees with Chronic Hepatitis B Virus Infection

Mason

Low

et al. 2009

J Virol

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“…Patients with predominantly nuclear HBcAg had higher levels of viral replication (8), whereas those with predominantly cytoplasmic HBcAg had significantly higher levels of biochemical and histological activities (9). However, some studies suggested that nuclear HBcAg might not be involved in HBV replication (1,11). In those studies, the majority of the patients had HBeAg-positive CHB.…”

Section: Discussionmentioning

confidence: 99%

“…Some studies suggested that cytoplasmic HBcAg was a more reliable marker of HBV replication than nuclear core HBcAg (1,11). Of the 35 intrahepatic-HBcAg-positive patients, 8 (22.9%) had a purely cytoplasmic distribution, 4 (11.4%) had a purely nuclear distribution, and 23 (65.7%) had a mixed cytoplasmic and nuclear distribution.…”

Section: Distribution Patterns Of Hbcag and Their Clinical And Patholmentioning

confidence: 99%

Core Antigen Expression Is Associated with Hepatic Necroinflammation in e Antigen-Negative Chronic Hepatitis B Patients with Low DNA Loads

Huang

Hung

Chan

et al. 2010

Clin Vaccine Immunol

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“…Typically, a large fraction of hepatocytes in the chronically HBV infected liver, including, but not limited to foci of altered hepatocytes (FAH) [20,21], do not contain detectable levels of virus antigens and nucleic acids [22][23][24][25][26][27][28][29][30][31][32], suggesting that these hepatocytes do not support HBV infection. Alternatively, some of these hepatocytes may express HBV surface antigen (HBsAg) in the absence of virus replication or expression of HBcAg.…”

Section: Introductionmentioning

confidence: 99%

Immune selection during chronic hepadnavirus infection

2007

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Purpose Late-stage outcomes of chronic hepatitis B virus (HBV) infection, including fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) result from persistent liver injury mediated by HBV antigen specific cytotoxic T lymphocytes (CTLs). Two other outcomes that often accompany chronic infection, the emergence of mutant viruses, including HBe-antigen negative (HBeAg (-)) HBV, and a reduction over time in the fraction of hepatocytes productively infected with HBV, may also result from persistent immune attack by antiviral CTLs. To gain insights into how these latter changes take place, we employed computer simulations of the chronically infected liver. Methods Computational programs were used to model the emergence of both virus-free hepatocytes and mutant strains of HBV. Results The computer modeling predicted that if cell-tocell spread of virus is an efficient process during chronic infections, an HBV mutant that replicated significantly more efficiently than the wild type would emerge as the prevalent virus in a few years, much more rapidly than observed, while a mutant that replicated with the same or lower efficiency would fail to emerge. Thus, either cell-tocell spread is inefficient or mutants do not replicate appreciably more efficiently than wild type. In contrast, with immune selection and a higher rate of killing of hepatocytes infected with wild-type virus, emergence of mutant virus can be explained without the need for a higher replication rate. Immune selection could also explain the emergence of virus-free hepatocytes that are unable to support HBV infection, since they should have a lower turnover rate than infected hepatocytes.

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Cytoplasmic (but not Nuclear) Hepatitis B Virus (HBV) Core Antigen Reflects HBV DNA Synthesis at the Level of the Infected Hepatocyte

Cited by 46 publications

References 8 publications

Detection of Clonally Expanded Hepatocytes in Chimpanzees with Chronic Hepatitis B Virus Infection

Detection of Clonally Expanded Hepatocytes in Chimpanzees with Chronic Hepatitis B Virus Infection

Core Antigen Expression Is Associated with Hepatic Necroinflammation in e Antigen-Negative Chronic Hepatitis B Patients with Low DNA Loads

Immune selection during chronic hepadnavirus infection

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