Limited Hepatitis B Virus Replication Space in the Chronically Hepatitis C Virus-Infected Liver

Wieland, Stefan; Asabe, Shinichi; Engle, Ronald E.; Purcell, Robert H.; Chisari, Francis V.

doi:10.1128/jvi.03553-13

Cited by 34 publications

(25 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our observation that innate immune activation restricts HBV infection is consistent with studies showing that HBV can be cleared from the liver in a cytokine-mediated, noncytotoxic manner (25,32), and that HBV replication is significantly reduced in chimpanzees chronically infected with HCV because of the induction of the type I IFN response (33). In contrast to the robust induction of ISGs in HBV-infected MPCCs, and to a lesser extent in iHeps, no ISG response was observed in HBV-permissive HepG2 cells overexpressing NTCP.…”

Section: Discussionsupporting

confidence: 78%

Modeling host interactions with hepatitis B virus using primary and induced pluripotent stem cell-derived hepatocellular systems

Shlomai

Schwartz

Ramanan³

et al. 2014

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

223

250

View full text Add to dashboard Cite

Hepatitis B virus (HBV) chronically infects 400 million people worldwide and is a leading driver of end-stage liver disease and liver cancer. Research into the biology and treatment of HBV requires an in vitro cell-culture system that supports the infection of human hepatocytes, and accurately recapitulates virus-host interactions. Here, we report that micropatterned cocultures of primary human hepatocytes with stromal cells (MPCCs) reliably support productive HBV infection, and infection can be enhanced by blocking elements of the hepatocyte innate immune response associated with the induction of IFN-stimulated genes. MPCCs maintain prolonged, productive infection and represent a facile platform for studying virus-host interactions and for developing antiviral interventions. Hepatocytes obtained from different human donors vary dramatically in their permissiveness to HBV infection, suggesting that factors-such as divergence in genetic susceptibility to infection-may influence infection in vitro. To establish a complementary, renewable system on an isogenic background in which candidate genetics can be interrogated, we show that inducible pluripotent stem cells differentiated into hepatocyte-like cells (iHeps) support HBV infection that can also be enhanced by blocking interferon-stimulated gene induction. Notably, the emergence of the capacity to support HBV transcriptional activity and initial permissiveness for infection are marked by distinct stages of iHep differentiation, suggesting that infection of iHeps can be used both to study HBV, and conversely to assess the degree of iHep differentiation. Our work demonstrates the utility of these infectious systems for studying HBV biology and the virus' interactions with host hepatocyte genetics and physiology.HBV persistence | innate immunity | viral hepatitis H epatitis B virus (HBV) is a small 3.2-kb DNA virus that selectively infects hepatocytes in the human liver (1). The global disease burden is large, with ∼400 million people chronically infected worldwide, of whom about one-third will develop severe HBV-related complications, such as cirrhosis and liver cancer. Lifelong treatment is often required because of the stable nature of viral episomal DNA, known as covalently closed circular DNA (cccDNA), which maintains basal levels in infected cell nuclei even upon nucleos(t)ide inhibitor treatment. To date, HBV research has been hampered by a distinct lack of robust infectious model systems that both support productive HBV infection and accurately mimic virus-host interactions. Recently, the bile acid pump sodium taurocholate cotransporting polypeptide (NTCP) has been identified as a receptor for both HBV and hepatitis D virus (2), and overexpression of NTCP in hepatoma cell lines renders them susceptible to HBV infection. However, hepatoma cells are known to be defective in many cellular pathways implicated in the innate immune response (3, 4), metabolism (5), and cell proliferation (6), which may contribute to published contradictory evidence regarding the e...

show abstract

Section: Discussionsupporting

confidence: 78%

Modeling host interactions with hepatitis B virus using primary and induced pluripotent stem cell-derived hepatocellular systems

Shlomai

Schwartz

Ramanan³

et al. 2014

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

223

250

View full text Add to dashboard Cite

show abstract

“…If and how HBV is detected by the innate immune system has remained an important yet unresolved issue. In contrast to many other viruses, HBV is generally thought to be a "stealth" virus because it does not induce a type I IFN response during natural or experimental infections (19)(20)(21)(22)(23)(24). This is thought to be related to the unique replication cycle of the virus.…”

mentioning

confidence: 99%

“…This adaptive response is able to clear the virus in the vast majority (90 to 95%) of immunocompetent adults (29). In addition to cytotoxic effector lymphocytes that directly kill infected cells, soluble immune effectors (such as type I and type III IFN, tumor necrosis factor alpha [TNF-␣], and interleukin 6 [IL-6]) elicit strong, noncytolytic antiviral effects targeting multiple stages of the HBV replication cycle, including transcriptional and posttranscriptional suppression of viral RNA expression, blocking of NC assembly, and destabilization of preformed NCs (24,25,(30)(31)(32)(33)(34)(35)(36)(37). Intriguingly, as demonstrated in an HBV transgenic-mouse model, IFN can also stimulate, rather than suppress, HBV gene expression and replication when viral replication levels are low (38), suggesting that HBV may have evolved to coopt the host antiviral response to enhance its own replication.…”

mentioning

confidence: 99%

Viral DNA-Dependent Induction of Innate Immune Response to Hepatitis B Virus in Immortalized Mouse Hepatocytes

Cui

Clark

Liu

et al. 2016

J Virol

View full text Add to dashboard Cite

Hepatitis B virus (HBV) infects hundreds of millions of people worldwide and causes acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. HBV is an enveloped virus with a relaxed circular (RC) DNA genome. In the nuclei of infected human hepatocytes, conversion of RC DNA from the incoming virion or cytoplasmic mature nucleocapsid (NC) to the covalently closed circular (CCC) DNA, which serves as the template for producing all viral transcripts, is essential to establish and sustain viral replication. A prerequisite for CCC DNA formation is the uncoating (disassembly) of NCs to expose their RC DNA content for conversion to CCC DNA. We report here that in an immortalized mouse hepatocyte cell line, AML12HBV10, in which RC DNA exposure is enhanced, the exposed viral DNA could trigger an innate immune response that was able to modulate viral gene expression and replication. When viral gene expression and replication were low, the innate response initially stimulated these processes but subsequently acted to shut off viral gene expression and replication after they reached peak levels. Inhibition of viral DNA synthesis or cellular DNA sensing and innate immune signaling diminished the innate response. These results indicate that HBV DNA, when exposed in the host cell cytoplasm, can function to trigger an innate immune response that, in turn, modulates viral gene expression and replication. IMPORTANCE Chronic infection by hepatitis B virus (HBV) afflicts hundreds of millions worldwide and is sustained by the episomal covalently closed circular (CCC) DNA in the nuclei of infected hepatocytes.Release of viral genomic DNA from cytoplasmic nucleocapsids (NCs) (NC disassembly or uncoating) is a prerequisite for its conversion to CCC DNA, which can also potentially expose the viral DNA to host DNA sensors and trigger an innate immune response. We have found that in an immortalized mouse hepatocyte cell line in which efficient CCC DNA formation was associated with enhanced exposure of nucleocapsid-associated DNA, the exposed viral DNA indeed triggered host cytoplasmic DNA sensing and an innate immune response that was able to modulate HBV gene expression and replication. Thus, HBV can, under select conditions, be recognized by the host innate immune response through exposed viral DNA, which may be exploited therapeutically to clear viral persistence. Hepatitis B virus (HBV) has infected approximately 2 billion people worldwide, with 350 million of them becoming chronically infected (1). Annually, 1 million fatalities are attributed to acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) caused by HBV. HBV is a small, enveloped DNA virus that contains a 3.2-kb, partially double-stranded (DS), relaxed circular (RC) DNA genome and replicates via an RNA intermediate, the pregenomic RNA (pgRNA). Upon infection, HBV RC DNA is converted to covalently closed circular (CCC) DNA in the nuclei of infected human hepatocytes, which serves as the transcriptional template for all viral RNAs, incl...

show abstract

“…Surprisingly, however, intrahepatic gene expression profiling in acutely HBV-infected chimpanzees revealed that HBV does not induce detectable ISGs or other cellular gene expression as it spreads throughout the liver (Fig. 1A) (Wieland et al 2004a(Wieland et al , 2014Wieland and Chisari 2005). This observation indicated that, unlike HCV, HBV acts like a "stealth virus," which is invisible to the innate immune system (Wieland et al 2004a;Wieland and Chisari 2005).…”

Section: Absence Of An Innate Response By Hbv-infected Cellsmentioning

confidence: 96%

The Chimpanzee Model for Hepatitis B Virus Infection

Wieland

2015

Cold Spring Harbor Perspectives in Medicine

Self Cite

View full text Add to dashboard Cite

Even before the discovery of hepatitis B virus (HBV), it was known that chimpanzees (Pan troglodytes) are susceptible to human hepatitis viruses. The chimpanzee is the only primate animal model for HBV infections. Much like HBV-infected human patients, chimpanzees can developacute andchronic HBVinfectionsand consequent hepatitis. Chimpanzees alsodevelop a cellular immune response similar to that observed in humans. For these reasons, the chimpanzee has proven to be an invaluable model for investigations on HBV-driven disease pathogenesis and also the testing of novel antiviral therapies and prophylactic approaches.

show abstract

Limited Hepatitis B Virus Replication Space in the Chronically Hepatitis C Virus-Infected Liver

Cited by 34 publications

References 30 publications

Modeling host interactions with hepatitis B virus using primary and induced pluripotent stem cell-derived hepatocellular systems

Modeling host interactions with hepatitis B virus using primary and induced pluripotent stem cell-derived hepatocellular systems

Viral DNA-Dependent Induction of Innate Immune Response to Hepatitis B Virus in Immortalized Mouse Hepatocytes

The Chimpanzee Model for Hepatitis B Virus Infection

Contact Info

Product

Resources

About