Immune selection during chronic hepadnavirus infection

Mason, William S.; Litwin, Sam; Jilbert, Allison R.

doi:10.1007/s12072-007-9024-3

Cited by 26 publications

(39 citation statements)

References 58 publications

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“…Previous investigations showed that HBV DNA in the host cell genome can produce enough surface antigen molecules for HDV virion assembly even in the absence of precore and pregenomic RNAs and regardless of an active HBV replication [32,33] . These cells, which still produce some of the viral products, may be selected through immune responses, appear as a result of a resolved infection or just due to the support of the infected cells for parts of the viral proteins such as envelope antigens but not the complete replication of the virus [33][34][35] . Nonetheless, regarding the role of HBV as an envelope provider, HDV nucleoproteins can be considered as competitors with HBV for HBsAg.…”

Section: Replicationmentioning

confidence: 99%

Molecular interactions between hepatitis B virus and delta virus

Shirvani-Dastgerdi¹

2015

WJV

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HBV HBsAgs. While HBsAg is the only protein required by HDV, the exact interaction sites between the S protein and pre-mature HDV are not well defined yet. In fact, these sites are distributed along the S protein with some hot spots for the envelopment process. Moreover, in most clinically studied samples, HDV infection is associated with a dramatically reduced HBV viral load, temporarily or permanently, while HBsAg resources are available for HDV packaging. Thus, beyond interacting with HBV envelope proteins, controlling mechanisms exist by which HDV inhibits HBV-DNA replication while allowing a selective transcription of HBV proteins. Here we discuss the molecular interaction sites between HBsAg and the HDV-RNP complex and address the proposed indirect mechanisms, which are employed by HBV and HDV to facilitate or inhibit each other's viral replication. Understanding molecular interactions between HBV and HDV may help to design novel therapeutic strategies for delta hepatitis. Core tip: Hepatitis D virus (HDV) causes accelerated liver disease in form of fulminant or chronic hepatitis in patients with hepatitis B virus (HBV) infection. HBV supports HDV replication by sharing its surface proteins. Even without overt HBV-DNA replication, transcription of HBV surface proteins (HBsAgs) remains stable in HDV infected cells, which is essential for assembly of HDV virions containing HBsAg proteins. HDV replication is oftentimes associated with a suppression of HBV-DNA levels, and several mechanisms have been suggested how HBV or HDV may influence each other's replication. Understanding molecular interactions between HBV and HDV may help to design novel therapeutic strategies. Molecular interactions between hepatitis B virus and delta virus AbstractAs a deficient virus due to the lack of envelope proteins, hepatitis D virus (HDV) causes chronic or fulminant "delta hepatitis" only in people with simultaneous hepatitis B virus (HBV) infection. HBV encodes three types of surface proteins known as small (S), medium (M) and large (L) envelope proteins. All three types of HBV surface antigens (HBsAgs) are present on HDV virions. The envelopment process of HDV occurs through interactions between the HDV ribonucleoprotein (RNP) complex and 36 EDITORIALSubmit a

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Section: Replicationmentioning

confidence: 99%

Molecular interactions between hepatitis B virus and delta virus

Shirvani-Dastgerdi¹

2015

WJV

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“…Thus, a number of HDV-infected hepatocytes apparently may not display markers of HBV replication. In addition, HDV is able to suppress HBV replication (2,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). The observations presented above indicate that HDV and HBV, while being present in the same liver, may not necessarily be present in the same cell.…”

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confidence: 95%

“…Normal hepatocytes that are apparently free of HBV replication markers but still express HBV envelope proteins can appear as a result of resolved HBV infection or via immunemediated selection. In addition, HCC cells may apparently no longer support HBV replication but can still support the production of envelope proteins from HBV integrants (3,(14)(15)(16)(25)(26)(27) (28)(29)(30)(31)(32)(33). In addition, the functional properties of integrant-derived HBV surface antigens (HBsAgs) remain to be fully evaluated (16, 29-31, 34, 35).…”

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confidence: 99%

Envelope Proteins Derived from Naturally Integrated Hepatitis B Virus DNA Support Assembly and Release of Infectious Hepatitis Delta Virus Particles

Freitas

Cunha

Menne

et al. 2014

J Virol

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A natural subviral agent of human hepatitis B virus (HBV), hepatitis delta virus (HDV), requires only the envelope proteins from HBV in order to maintain persistent infection. HBV surface antigens (HBsAgs) can be produced either by HBV replication or from integrated HBV DNA regardless of replication. The functional properties of the integrant-generated HBsAgs were examined using two human hepatocellular carcinoma-derived cell lines, Hep3B and PLC/PRF/5, that contain HBV integrants but do not produce HBV virions and have no signs of HBV replication. Both cell lines were able to support HDV replication and assembly/egress of HDV virions. Neither of the cell lines was able to produce substantial amounts of the pre-S1-containing HDV particles. HDV virions assembled in PLC/PRF/5 cells were able to infect primary human hepatocytes, while Hep3B-derived HDV appeared to be noninfectious. These results correlate with the findings that the entire open reading frame (ORF) for the large (L) envelope protein that is essential for infectivity is present on HBV RNAs from PLC/PRF/5 cells, while an L protein ORF that was truncated and fused to inverted precore sequences was found using RNAs from Hep3B cells. This study demonstrates for the first time that at least some of the HBV DNA sequence naturally integrated during infection can produce functional small and large envelope proteins capable of the formation of infectious HDV virions. Our data indicate that in vivo chronic HDV infection can persist in the absence of HBV replication (or when HBV replication is profoundly suppressed) if functional envelope proteins are supplied from HBV integrants. IMPORTANCEThe study addresses the unique mechanism of HDV persistence in the absence of ongoing HBV replication, advances our understanding of HDV-HBV interactions, and supports the implementation of treatments directly targeting HDV for HDV/HBV-infected individuals. Hepatitis delta virus (HDV) is a significant human pathogen, with approximately 20 million people worldwide being chronic carriers. HDV is a natural subviral agent of human hepatitis B virus (HBV) that requires from its helper hepadnavirus only the envelope proteins in order to form virions and infect hepatocytes via the HBV receptor. In infected livers, HDV coexists with HBV. Chronic HBV infection remains a main risk factor for hepatocellular carcinoma (HCC) and is associated with more than half of all HCC cases (1-4). Concomitant HDV infection is able to inflict additional liver damage associated with accelerated liver disease, cirrhosis, liver failure, and HCC (5-11). Treatment with alpha interferon is beneficial for only a subset of HDV carriers. There are no treatments in clinical practice that directly target HDV, and practically none of the anti-HBV drugs blocks HDV infection (5,12,13). In livers chronically infected with HBV, as many as 90% of hepatocytes may appear to be free of HBV replication markers. HBV-infected individuals can support HDV infection regardless of the presence of HBV replication markers...

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“…Some of the virus-free hepatocytes form foci of altered hepatocytes (FAH) with morphology similar to that of liver cancer cells and are considered premalignant. In addition, the cells of hepadnavirus-induced HCCs often were reported to be virus free as well (1,4,(15)(16)(17)(18)(19)(20)(21)(22)(23). In contrast, several previous studies reported the presence of hepadnaviral , making the issue still controversial.…”

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confidence: 99%

Superinfection with Woodchuck Hepatitis Virus Strain WHVNY of Livers Chronically Infected with Strain WHV7

Rodrigues

Freitas

Kallakury

et al. 2015

J Virol

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The determinants of the maintenance of chronic hepadnaviral infection are yet to be fully understood. A long-standing unresolved argument in the hepatitis B virus (HBV) research field suggests that during chronic hepadnaviral infection, cell-to-cell spread of hepadnavirus is at least very inefficient (if it occurs at all), virus superinfection is an unlikely event, and chronic hepadnavirus infection can be maintained exclusively via division of infected hepatocytes in the absence of virus spread. Superinfection exclusion was previously shown for duck HBV, but it was not demonstrated for HBV or HBV-related woodchuck hepatitis virus (WHV). Three woodchucks, which were chronically infected with the strain WHV7 and already developed WHV-induced hepatocellular carcinomas (HCCs), were superinfected with another WHV strain, WHVNY. Six weeks after the superinfection, the woodchucks were sacrificed and tissues of the livers and HCCs were examined. The WHVNY superinfection was demonstrated by using WHV strain-specific PCR assays and ( Worldwide, approximately four hundred million people are chronic carriers of human hepatitis B virus (HBV), which is a prototype hepadnavirus. Chronic HBV infection is a main risk factor of hepatocellular carcinoma (HCC), and it is associated with more than 50% of all known cases of HCC (1-14). During the early stage of hepadnaviral infection, virtually the entire liver becomes infected with a hepadnavirus within several weeks. However, during chronic infection, areas of apparently hepadnavirusfree hepatocytes were observed in HBV carrier humans and chimpanzees and also in woodchucks chronically infected with woodchuck hepatitis virus (WHV), which is closely related to HBV. The hepadnavirus-free hepatocytes tested negative for (i) the hepadnavirus core antigen (by immunostaining) and (ii) the viral DNA (by in situ hybridization) regardless of the ongoing viremia. In HBV carrier humans, up to 90% of all hepatocytes could appear to be HBV free. Some of the virus-free hepatocytes form foci of altered hepatocytes (FAH) with morphology similar to that of liver cancer cells and are considered premalignant. In addition, the cells of hepadnavirus-induced HCCs often were reported to be virus free as well (1,4,(15)(16)(17)(18)(19)(20)(21)(22)(23). In contrast, several previous studies reported the presence of hepadnaviral , making the issue still controversial. The observations of apparent hepadnavirus-free HCC cells and hepatocytes, along with the analysis of the kinetics of the emergence of drug-resistant HBV mutants, laid the foundation for a long-standing unresolved argument in the HBV field that during chronic infection, cell-to-cell spread of a hepadnavirus is at least very inefficient (if it occurs at all), and superinfection is an un-

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Immune selection during chronic hepadnavirus infection

Cited by 26 publications

References 58 publications

Molecular interactions between hepatitis B virus and delta virus

Molecular interactions between hepatitis B virus and delta virus

Envelope Proteins Derived from Naturally Integrated Hepatitis B Virus DNA Support Assembly and Release of Infectious Hepatitis Delta Virus Particles

Superinfection with Woodchuck Hepatitis Virus Strain WHVNY of Livers Chronically Infected with Strain WHV7

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