Diverse Virus and Host-Dependent Mechanisms Influence the Systemic and Intrahepatic Immune Responses in the Woodchuck Model of Hepatitis B

Michalak, Tomasz I.

doi:10.3389/fimmu.2020.00853

Cited by 17 publications

(29 citation statements)

References 158 publications

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“…Placebo treatment was not associated with changes in the intrahepatic transcription of IFN-α, IFN-β, and IFN-γ. This is consistent with a diminished or impaired antiviral immune response usually present during CHB in woodchucks [28,33,35,[80][81][82] and patients [18,83,84], suggesting that the high levels of virions and subviral, surface-containing particles, and possibly of e antigen, are implicated in the maintenance of immunologic tolerance against hepadnaviruses at multiple levels, including DCs [50][51][52]. In agreement with this, ETV had no effect on antigenemia in the present study, and thus was unable to broadly induce IFNs in woodchucks.…”

Section: Discussionsupporting

confidence: 90%

“…Comparable to HBV, WHV causes age-dependent acute and chronic outcomes of infection, and experimental infection of neonatal woodchucks resembles the vertical transmission route of HBV in humans [ 25 , 28 , 29 ]. Immunopathogenesis and liver disease progression to HCC mediated by WHV in woodchucks parallels HBV infection in humans more so than in any other animal model currently available for HBV research [ 25 , 28 , 30 , 31 , 32 , 33 , 34 , 35 ]. Furthermore, woodchucks are fully immunocompetent and the animal model is supported by the recent identification of the liver transcriptome and genome [ 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

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Treatment with the Immunomodulator AIC649 in Combination with Entecavir Produces Antiviral Efficacy in the Woodchuck Model of Chronic Hepatitis B

Korolowicz

Suresh

et al. 2021

Viruses

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As current interventions for chronic hepatitis B (CHB) rarely induce cure, more effective drugs are needed. Short-term treatment of woodchucks with the novel immunomodulator AIC649, a parapoxvirus-based stimulator of toll-like receptor 9 dependent and independent pathways, has been shown to reduce viral DNA and surface antigen via a unique, biphasic response pattern. The present study evaluated long-term AIC649 treatment in combination with Entecavir for potency and safety in woodchucks. AIC649 monotreatment induced modest reductions in serum viral DNA and surface and e antigens that were associated with the same biphasic response pattern previously observed. Entecavir monotreatment reduced transiently viremia but not antigenemia, while AIC649/Entecavir combination treatment mediated superior viral control. Undetectability of viral antigens and elicitation of antibodies in AIC649/Entecavir-treated woodchucks correlated with the expression of interferons and suppression of viral replication in liver. Combination treatment was well tolerated, and liver enzyme elevations were minor and transient. It was concluded that the AIC649-mediated effects were most likely based on an improvement and/or reconstitution of antiviral immune responses that are typically deficient in CHB. As a combination partner to Entecavir, the antiviral efficacy of AIC649 was markedly enhanced. This preclinical study supports future evaluation of AIC649 for treatment of human CHB.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Treatment with the Immunomodulator AIC649 in Combination with Entecavir Produces Antiviral Efficacy in the Woodchuck Model of Chronic Hepatitis B

Korolowicz

Suresh

et al. 2021

Viruses

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“…injection with WHV at doses lower than 1000 virions, which can trigger HCC in the setting of seemingly entirely normal liver function and morphology, while a low level WHV replication and integrated viral DNA are detectable in the immune system and the liver [16] . With a similar frequency of about 20%, HCC develops in woodchucks recovered from an acute episode of hepatitis in which traces of infectious WHV persist for life [15] . This infection form is termed as secondary occult infection (SOI) and remains serum WHV DNA reactive at levels below 100-200 copies or virus genome equivalents (vge) per mL.…”

Section: Introductionmentioning

confidence: 99%

“…This unapparent form of infection, named as occult HBV infection (OBI), is a consequence of enduring residual virus replication that is accompanied by traces of circulating HBV DNA in the absence of serum HBsAg detectable by currently available clinical tests [13] . This also is clearly apparent in woodchucks experimentally infected with woodchuck hepatitis virus (WHV), which represent overall an excellent model of molecular and immunological events and pathological outcomes encountered in HBV-infected humans [14,15] . This is well exemplified in primary occult infection (POI) induced by an intravenous (i.v.)…”

Section: Introductionmentioning

confidence: 99%

Earliest hepatitis B virus-hepatocyte genome integration: sites, mechanism, and significance in carcinogenesis

Chauhan¹,

Michalak²

2021

Self Cite

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Hepatocellular carcinoma (HCC) is the fifth most widespread cancer responsible for one fourth of cancer-related deaths globally. Persistent infection with hepatitis B virus (HBV) remains the main cause of HCC summing up to 50% of its causative etiology. Our recent studies, supported by findings from others, uncovered that HBV and its close relative woodchuck hepatitis virus (WHV) integrate into hepatocyte genome almost immediately, hence in minutes after infection. Retrotransposons and genes with translocation potential were found to be frequent sites of HBV insertions, suggesting a mechanism of HBV DNA spread across liver genome from the earliest stages after virus invasion. Many other genes were identified as the sites of early hepadnavirus merges in human hepatocyte-like lines infected de novo with HBV and in natural woodchuck WHV infection model. It was uncovered that head-to-tail joins (HTJs) prevail among the earliest virus-host fusions, implying their formation via the non-homologous-end-joining (NHEJ) pathway. Overlapping homologous junctions resulting from the micro-homology-mediated-overlapping-joining (MHMOJ) were rarely detected. Formation of the initial HTJs coincided with strong induction of reactive oxygen species (ROS) and transient appearance of inducible nitric oxide (iNOS). This was accompanied by cell DNA damage and activation of the poly(ADP-ribose) polymerase 1 (PARP1)-mediated host DNA repair machinery, which may explain predominant HTJ format of the first virushost fusions. Identification of initial integration sites and resulting alterations in hepatocyte phenotype may pave a way to discovery of reliable markers of HBV-triggered HCC, including HCC resulting from occult HBV infection. Our research strongly argues that HBV is an ultimate human carcinogen capable of initiation of a pro-oncogenic process immediately after first contact with a susceptible host.

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“…While some of these studies provided evidence for the prevention and treatment of liver disease progression[ 37 , 38 ], evaluation of interventions directly targeting liver tumors in woodchucks for the treatment of HCC is limited. Since immunopathogenesis and liver disease progression to HCC induced by WHV parallels HBV infection in humans more so than in any other animal model currently available for HBV research[ 30 , 34 , 38 - 40 ], woodchucks with established liver tumors have been further applied in the improvement of imaging and ablation techniques and in the evaluation of new therapeutic approaches for the treatment of human HCC. The purpose of this review is to highlight the woodchuck as an animal model for hepatitis virus-induced carcinogenesis and treatment of HCC in patients with chronic HBV infection.…”

Section: Introductionmentioning

confidence: 99%

Application of the woodchuck animal model for the treatment of hepatitis B virus-induced liver cancer

Suresh¹,

Menne²

2021

WJGO

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This review describes woodchucks chronically infected with the woodchuck hepatitis virus (WHV) as an animal model for hepatocarcinogenesis and treatment of primary liver cancer or hepatocellular carcinoma (HCC) induced by the hepatitis B virus (HBV). Since laboratory animal models susceptible to HBV infection are limited, woodchucks experimentally infected with WHV, a hepatitis virus closely related to HBV, are increasingly used to enhance our understanding of virus-host interactions, immune response, and liver disease progression. A correlation of severe liver pathogenesis with high-level viral replication and deficient antiviral immunity has been established, which are present during chronic infection after WHV inoculation of neonatal woodchucks for modeling vertical HBV transmission in humans. HCC in chronic carrier woodchucks develops 17 to 36 mo after neonatal WHV infection and involves liver tumors that are comparable in size, morphology, and molecular gene signature to those of HBV-infected patients. Accordingly, woodchucks with WHV-induced liver tumors have been used for the improvement of imaging and ablation techniques of human HCC. In addition, drug efficacy studies in woodchucks with chronic WHV infection have revealed that prolonged treatment with nucleos(t)ide analogs, alone or in combination with other compounds, minimizes the risk of liver disease progression to HCC. More recently, woodchucks have been utilized in the delineation of mechanisms involved in innate and adaptive immune responses against WHV during acute, self-limited and chronic infections. Therapeutic interventions based on modulating the deficient host antiviral immunity have been explored in woodchucks for inducing functional cure in HBV-infected patients and for reducing or even delaying associated liver disease sequelae, including the onset of HCC. Therefore, woodchucks with chronic WHV infection constitute a well-characterized, fully immunocompetent animal model for HBV-induced liver cancer and for preclinical evaluation of the safety and efficacy of new modalities, which are based on chemo, gene, and immune therapy, for the prevention and treatment of HCC in patients for which current treatment options are dismal.

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Diverse Virus and Host-Dependent Mechanisms Influence the Systemic and Intrahepatic Immune Responses in the Woodchuck Model of Hepatitis B

Cited by 17 publications

References 158 publications

Treatment with the Immunomodulator AIC649 in Combination with Entecavir Produces Antiviral Efficacy in the Woodchuck Model of Chronic Hepatitis B

Treatment with the Immunomodulator AIC649 in Combination with Entecavir Produces Antiviral Efficacy in the Woodchuck Model of Chronic Hepatitis B

Earliest hepatitis B virus-hepatocyte genome integration: sites, mechanism, and significance in carcinogenesis

Application of the woodchuck animal model for the treatment of hepatitis B virus-induced liver cancer

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