Hepatocyte turnover during resolution of a transient hepadnaviral infection

Summers, Jesse; Jilbert, Allison R.; Yang, Wengang; Aldrich, Carol E.; Saputelli, Jeffry; Litwin, Samuel; Toll, Eugene; Mason, William S.

doi:10.1073/pnas.1635109100

Cited by 162 publications

(162 citation statements)

References 40 publications

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“…4 On the other hand, histological data indicate that liver cell death and regeneration both occur in transiently and chronically infected livers, suggesting that clearance of hepadnavirus infection is accompanied by immune-mediated destruction of infected hepatocytes. 12, 13 Yet it has been shown that very low levels of cccDNA can persist indefinitely in a small number of liver cells, possibly explaining the lifelong immune response to HBV despite clinical resolution of infection 14 and the clinical relapse of hepatitis B during chemotherapy and other immunosuppressive regimens.…”

Section: Nfection With Hepatitis B Virus (Hbv) Causes Acutementioning

confidence: 99%

Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B

et al. 2006

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I nfection with hepatitis B virus (HBV) causes acute and chronic hepatitis and is strongly associated with the development of cirrhosis and hepatocellular carcinoma. Immediately after infection of hepatocytes, the viral DNA is transferred to the nucleus, where the viral polymerase is removed, and the double-stranded, open circular DNA is converted to a covalently closed circular DNA molecule (cccDNA). During chronic HBV infection (CH-B), cccDNA accumulates in hepatocyte nuclei, apparently at a level of about 5-50 copies per cell, where it persists as a minichromosome and functions as the template for the transcription of viral genes. 1 The RNA pregenome, in addition to producing capsid and polymerase proteins, becomes encapsidated and is reverse-transcribed. A particularity of the hepadnavirus life cycle is that DNA-containing nucleocapsids can either recycle back to the nucleus to amplify and maintain the pool of cccDNA or become enveloped and secreted into the blood, where new viral particles can spread to other hepatocytes. 2,3 Because cccDNA is the transcriptional template of the virus, it is required for maintenance of HBV infection.Evidence from the woodchuck hepatitis virus system indicated that the pool of cccDNA persisted even when viral production was strongly reduced by the presence of nucleoside analogues. 4,5 Woodchuck studies 6,7 and recent

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Section: Nfection With Hepatitis B Virus (Hbv) Causes Acutementioning

confidence: 99%

Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B

et al. 2006

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“…Since hepadnavirus infection is not cytopathic, elimination of hepadnavirus-infected hepatocytes requires immune attack by virus antigen-specific CTLs, leading to the elimination of cccDNA directly by hepatocyte death or indirectly during compensatory hepatocyte proliferation [6]. Whether significant cccDNA loss occurs in the absence of hepatocyte turnover (i.e., hepatocyte death and compensatory proliferation) remains unclear [7].…”

Section: Introductionmentioning

confidence: 99%

“…Whether significant cccDNA loss occurs in the absence of hepatocyte turnover (i.e., hepatocyte death and compensatory proliferation) remains unclear [7]. We and others have reported that resolution of transient hepadnavirus infections involves immunemediated attack on large numbers of hepatocytes and significant turnover of the hepatocyte population [6,8], with turnover of up to 10% of the hepatocyte population per day [6,9,10].…”

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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“…In the duck hepatitis B virus (DHBV) model, the cccDNA level is regulated by the viral envelope proteins (6). Evidence from the woodchuck hepatitis virus (WHV) system suggests that cccDNA clearance is tightly associated with the destruction and turnover of infected hepatocytes (7,8). The possibility that cccDNA may also be susceptible to control by immune-mediated noncytolytic mechanisms is an open question at this time, at least partially due to uncertainty regarding its half-life.…”

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confidence: 99%

Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees

Wieland

Spangenberg²,

Thimme³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

206

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We have previously shown that hepatitis B virus (HBV) replication is controlled by noncytolytic mechanisms that depend primarily on the effector functions of the CD8 ؉ T cell response, especially the production of IFN-␥ in the liver. The mechanisms that control the nuclear pool of viral covalently closed circular DNA (cccDNA) transcriptional template of HBV, which must be eliminated to eradicate infection, have been difficult to resolve. To examine those mechanisms, we quantitated intrahepatic HBV cccDNA levels in acutely infected chimpanzees whose virological, immunological, and pathological features were previously described. Our results demonstrate that the elimination kinetics of the cccDNA are more rapid than the elimination of HBV antigen-positive hepatocytes during the early phase of viral clearance, and they coincide with the influx of small numbers of IFN-␥ producing CD8 ؉ T cells into the liver. In contrast, terminal clearance of the cccDNA is associated with the peak of liver disease and hepatocellular turnover and with a surge of IFN-␥ producing CD8 ؉ T cells in the liver. Collectively, these results suggest that cccDNA clearance is a two-step process mediated by the cellular immune response. The first step reduces the pool of cccDNA molecules noncytolytically, probably by eliminating their relaxed circular DNA precursors and perhaps by destabilizing them. The second step enhances this process by destroying infected hepatocytes and triggering their turnover. Surprisingly, despite this multipronged response, traces of cccDNA persist indefinitely in the liver, likely providing a continuous antigenic stimulus that confers lifelong immunity.H epadnaviruses are small enveloped hepatotropic DNA viruses containing a relaxed circular DNA genome, which is converted into a covalently closed circular DNA (cccDNA) episome in the nucleus of infected cells (1). The cccDNA molecule serves as the transcriptional template for production of viral RNAs that are exported to the cytoplasm and encode the viral structural and nonstructural proteins, including the reverse transcriptase͞DNA polymerase. Reverse transcription of the viral pregenomic (pg)RNA and second-strand DNA synthesis occurs in the cytoplasm within viral capsids formed by the HBV core protein (HBcAg). Capsids containing the mature relaxed circular DNA genome are either enveloped and exported as virions, or they deliver their DNA content to the nucleus, thereby amplifying the pool of cccDNA molecules to 10-50 copies per cell (2-5). The factors that regulate the cccDNA content of infected cells are not very well understood. In the duck hepatitis B virus (DHBV) model, the cccDNA level is regulated by the viral envelope proteins (6). Evidence from the woodchuck hepatitis virus (WHV) system suggests that cccDNA clearance is tightly associated with the destruction and turnover of infected hepatocytes (7,8). The possibility that cccDNA may also be susceptible to control by immune-mediated noncytolytic mechanisms is an open question at this time, at least partiall...

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Hepatocyte turnover during resolution of a transient hepadnaviral infection

Cited by 162 publications

References 40 publications

Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B

Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B

Immune selection during chronic hepadnavirus infection

Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees

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