This review describes the woodchuck and the woodchuck hepatitis virus (WHV) as an animal model for pathogenesis and therapy of chronic hepatitis B virus (HBV) infection and disease in humans. The establishment of wood...This review describes the woodchuck and the woodchuck hepatitis virus (WHV) as an animal model for pathogenesis and therapy of chronic hepatitis B virus (HBV) infection and disease in humans. The establishment of woodchuck breeding colonies, and use of laboratory-reared woodchucks infected with defined WHV inocula, have enhanced our understanding of the virology and immunology of HBV infection and disease pathogenesis, including major sequelae like chronic hepatitis and hepatocellular carcinoma. The role of persistent WHV infection and of viral load on the natural history of infection and disease progression has been firmly established along the way. More recently, the model has shed new light on the role of host immune responses in these natural processes, and on how the immune system of the chronic carrier can be manipulated therapeutically to reduce or delay serious disease sequelae through induction of the recovery phenotype. The woodchuck is an outbred species and is not well defined immunologically due to a limitation of available host markers. However, the recent development of several key host response assays for woodchucks provides experimental opportunities for further mechanistic studies of outcome predictors in neonatal- and adult-acquired infections. Understanding the virological and immunological mechanisms responsible for resolution of self-limited infection, andfor the onset and maintenance of chronic infection, will greatly facilitate the development of successful strategies for the therapeutic eradication of established chronic HBV infection. Likewise, the results of drug efficacy and toxicity studies in the chronic carrier woodchucks are predictive for responses of patients chronically infected with HBV. Therefore, chronic WHV carrier woodchucks provide a well-characterized mammalian model for preclinical evaluation of the safety and efficacy of drug candidates, experimental therapeutic vaccines, and immunomodulators for the treatment and prevention of HBV disease sequelae.展开更多
AIM： To demonstrate the feasibility of using woodchuck samples on human microarrays, to provide insight into pathways involving positron emission tomography （PET） imaging tracers and to identify genes that could be...AIM： To demonstrate the feasibility of using woodchuck samples on human microarrays, to provide insight into pathways involving positron emission tomography （PET） imaging tracers and to identify genes that could be potential molecular imaging targets for woodchuck hepatocellular carcinoma. METHODS： Labeled cRNA from woodchuck tissue samples were hybridized to Affymetrix U133 plus 2.0 GeneChips. Ten genes were selected for validation using quantitative RT-PCR and literature review was made. RESULTS： Testis enhanced gene transcript （BAX Inhibitor 1）, alpha-fetoprotein, isocitrate dehydrogenase 3 （NAD＋） beta, acetyI-CoA synthetase 2, carnitine palmitoyltransferase 2, and N-myc2 were up-regulated and spermidine/spermine N1-acetyltransferase was down-regulated in the woodchuck HCC. We also found previously published results supporting 8 of the 10 most up-regulated genes and all 10 of the 10 most downregulated genes. CONCLUSION： Many of our microarray results were validated using RT-PCR or literature search. Hence, we believe that woodchuck HCC and non-cancerous liver samples can be used on human microarrays to yield meaningful results.展开更多
INTRODUCTIONHepatocellular carcinoma(HCC)is one of the major causes of death in the word.The mechanism of carcinogenesis is unknown,although it is widely accepted that HBV and HCV are clsely related to liver cancer[1-...INTRODUCTIONHepatocellular carcinoma(HCC)is one of the major causes of death in the word.The mechanism of carcinogenesis is unknown,although it is widely accepted that HBV and HCV are clsely related to liver cancer[1-5[1-5].Previously,a variety of studies have described the differences in gene expression which distinguished tumor from nontumor[6-11].Cloning of the genes,especially the genes associated with HBV and HCV,is still very important to account for the development of liver cancer.展开更多
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...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.展开更多
The woodchuck model is an excellent animal model to study hepadnaviral infection. The new progresses in this model made possible to examine the T-cell mediated immune responses in acute and chronic hepadnaviral infect...The woodchuck model is an excellent animal model to study hepadnaviral infection. The new progresses in this model made possible to examine the T-cell mediated immune responses in acute and chronic hepadnaviral infection. Recently, a new assay for cytotoxic T-cells based on detection of CD107 was established for the woodchuck model. In addition, new immunotherapeutic approaches based on combination of potent antiviral treatment and DNA-protein vaccines were proven to be useful for treatment of chronic hepatitis B.展开更多
The most commonly used preclinical models of hepatocellular carcinoma(HCC)are limited for use in testing of intra-arterial therapies such as transarterial chemoembolization and radioembolization.Issues encountered wit...The most commonly used preclinical models of hepatocellular carcinoma(HCC)are limited for use in testing of intra-arterial therapies such as transarterial chemoembolization and radioembolization.Issues encountered with the more commonly used animal models include dissimilarity in their disease development compared with humans and the size of the vasculature which can make intra-arterial therapy testing difficult or impossible.Here we describe the suitability of the woodchuck HCC model for testing of intra-arterial therapies.We describe the techniques for pre-embolization imaging assessment using CT and MRI,technical tips on performing angiography and embolization,and pathological assessment of treated liver.展开更多
Cytosolic retinoic acid-inducible gene I（RIG-I） is an important innate immune RNA sensor and can induce antiviral cytokines, e.g., interferon-β（IFN-β）. Innate immune response to hepatitis B virus（HBV） plays a ...Cytosolic retinoic acid-inducible gene I（RIG-I） is an important innate immune RNA sensor and can induce antiviral cytokines, e.g., interferon-β（IFN-β）. Innate immune response to hepatitis B virus（HBV） plays a pivotal role in viral clearance and persistence. However, knowledge of the role that RIG-I plays in HBV infection is limited. The woodchuck is a valuable model for studying HBV infection. To characterize the molecular basis of woodchuck RIG-I（w RIG-I）, we analyzed the complete coding sequences（CDSs） of w RIG-I, containing 2778 base pairs that encode 925 amino acids. The deduced w RIG-I protein was 106.847 k D with a theoretical isoelectric point（p I） of 6.07, and contained three important functional structures [caspase activation and recruitment domains（CARDs）, DEx D/H-box helicases, and a repressor domain（RD）]. In woodchuck fibroblastoma cell line（WH12/6）, w RIG-I-targeted small interfering RNA（si RNA） down-regulated RIG-I and its downstrean effector–IFN-β transcripts under RIG-I＇ ligand, 5＇-ppp double stranded RNA（ds RNA） stimulation. We also measured m RNA levels of w RIG-I in different tissues from healthy woodchucks and in the livers from woodchuck hepatitis virus（WHV）-infected woodchucks. The basal expression levels of w RIG-I were abundant in the kidney and liver. Importantly, w RIG-I was significantly up-regulated in acutely infected woodchuck livers, suggesting that RIG-I might be involved in WHV infection. These results may characterize RIG-I in the woodchuck model, providing a strong basis for further study on RIG-I-mediated innate immunity in HBV infection.展开更多
Woodchuck hepatitis virus (WHV) is molecularly and pathogenically closely related to hepatitis B virus (HBV).Both viruses display tropism towards hepatocytes and cells of the immune system and cause similar liver path...Woodchuck hepatitis virus (WHV) is molecularly and pathogenically closely related to hepatitis B virus (HBV).Both viruses display tropism towards hepatocytes and cells of the immune system and cause similar liver pathology,where acute hepatitis can progress to chronic hepatitis and to hepatocellular carcinoma (HCC).Two forms of occult hepadnaviral persistence were identified in the woodchuck-WHV model:secondary occult infection (SOI) and primary occult infection (POI).SOI occurs after resolution of a serologically apparent infection with hepatitis or after subclinical serologically evident virus exposure.POI is caused by small amounts of virus and progresses without serological infection markers,but the virus genome and its replication are detectable in the immune system and with time in the liver.SOI can be accompanied by minimal hepatitis,while the hallmark of POI is normal liver morphology.Nonetheless,HCC develops in about 20% of animals with SOI or POI within 3 to 5 years.The virus persists throughout the lifespan in both SOI and POI at serum levels rarely greater than 100 copies/mL,causes hepatitis and HCC when concentrated and administered to virus-na(i)ve woodchucks.SOI is accompanied by virusspecific T and B cell immune responses,while only virusspecific T cells are detected in POI.SOI coincides with protection against reinfection,while POI does not and hepatitis develops after challenge with liver pathogenic doses >1000 virions.Both SOI and POI are associated with virus DNA integration into the liver and the immune system genomes.Overall,SOI and POI are two distinct forms of silent hepadnaviral persistence that share common characteristics.Here,we review findings from the woodchuck model and discuss the relevant observations made in human occult HBV infection (OBI).展开更多
Even with an effective vaccine, an estimated 240 million people are chronically infected with hepatitis B virus （HBV） worldwide. Current antiviral therapies, including interferon and nucleot（s）ide analogues, rarel...Even with an effective vaccine, an estimated 240 million people are chronically infected with hepatitis B virus （HBV） worldwide. Current antiviral therapies, including interferon and nucleot（s）ide analogues, rarely cure chronic hepatitis B. Animal models are very crucial for understanding the pathogenesis of chronic hepatitis B and developing new therapeutic drugs or strategies. HBV can only infect humans and chimpanzees, with the use of chimpanzees in HBV research strongly restricted. Thus, most advances in HBV research have been gained using mouse models with HBV replication or infection or models with HBV-related hepadnaviral infection. This review summarizes the animal models currently available for the study of HBV infection.展开更多
Chronic hepatitis B virus(CHB) is currently treated with either interferon-based or nucleot(s)idebased antiviral therapies.However,treatment with pegylated interferon alpha results in a durable antiviral response in o...Chronic hepatitis B virus(CHB) is currently treated with either interferon-based or nucleot(s)idebased antiviral therapies.However,treatment with pegylated interferon alpha results in a durable antiviral response in only about 30%patients and is associated with side effects.Most patients receiving nucleot(s)ide analogue treatment do not establish long-term,durable control of Infection and have rebounding viremia after cessation of therapy.Thus,novel therapy strategies are necessary to achieve the induction of potent and durable antiviral immune responses of the patients which can maintain long-term control of viral replication.Therapeutic vaccination of HBV carriers is a promising strategy for the control of hepatitis B.Here the authors review new therapeutic vaccination strategies to treat chronic hepatitis B which may be introduced for patient treatment in the future.展开更多
Chronic active hepatitis(CAH) is acknowledged as an imperative risk factor for the development of liver injury and hepatocellular carcinoma.The histological end points of CAH are chronic inflammation,fibrosis and cirr...Chronic active hepatitis(CAH) is acknowledged as an imperative risk factor for the development of liver injury and hepatocellular carcinoma.The histological end points of CAH are chronic inflammation,fibrosis and cirrhosis which are coupled with increased DNA synthesis in cirrhotic vs healthy normal livers.The potential mechanism involved in CAH includes a combination of processes leading to liver cell necrosis,inflammation and cytokine production and liver scaring(fibrosis).The severity of liver damage is regulated by Hepatitis B virus genotypes and viral components.The viral and cellular factors that contribute to liver injury are discussed in this article.Liver injury caused by the viral infection affects many cellular processes such as cell signaling,apoptosis,transcription,DNA repair which in turn induce radical effects on cell survival,growth,transformation and maintenance.The consequence of such perturbations is resulted in the alteration of bile secretion,gluconeogenesis,glycolysis,detoxification and metabolism of carbohydrates,proteins,fat and balance of nutrients.The identification and elucidation of the molecular pathways perturbed by the viral proteins are important in order to design effective strategy to minimize and/or restore the hepatocytes injury.展开更多
2',3'-dideoxyguanosine(DoG) has been demonstrated to inhibit duck hepatitis B virus(DHBV) replication in vivo in a duck model of HBV infection. In the current study, the in vitro antiviral effects of DoG on hu...2',3'-dideoxyguanosine(DoG) has been demonstrated to inhibit duck hepatitis B virus(DHBV) replication in vivo in a duck model of HBV infection. In the current study, the in vitro antiviral effects of DoG on human and animal hepadnaviruses were investigated. Our results showed that DoG effectively inhibited HBV, DHBV, and woodchuck hepatitis virus(WHV)replication in hepatocyte-derived cells in a dose-dependent manner, with 50% effective concentrations(EC50) of 0.3 ± 0.05, 6.82 ± 0.25, and 23.0 ± 1.5 lmol/L, respectively. Similar to other hepadnaviral DNA polymerase inhibitors,DoG did not alter the levels of intracellular viral RNA but induced the accumulation of a less-than-full-length viral RNA species, which was recently demonstrated to be generated by RNase H cleavage of pgRNA. Furthermore, using a transient transfection assay, DoG showed similar antiviral activity against HBV wild-type, 3TC-resistant rtA181 V, and adefovirresistant rtN236T mutants. Our results suggest that DoG has potential as a nucleoside analogue drug with anti-HBV activity.展开更多
The clinical utility of positron emission tomography (PET) imaging for liver cancer applications is not clearly defined either for diagnosis or treatment assessment. Previous clinical studies demonstrated that fluorod...The clinical utility of positron emission tomography (PET) imaging for liver cancer applications is not clearly defined either for diagnosis or treatment assessment. Previous clinical studies demonstrated that fluorodeoxyglucose (FDG) did not show uptake in some hepatocellular carcinoma (HCC) while acetate showed uptake. Pre-imaging fasting is required for clinical PET imaging with FDG. No studies were done to confirm the effect of fasting on acetate uptake in HCC for PET imaging. We investigated this situation with a woodchuck model of viral infection-induced HCC. Methods: Four tumor-bearing and one control woodchucks were involved in this study. They were first imaged by PET in fed state followed by another imaging session one week later when they were fasted over-night. Some animals also had FDG- PET scan that was acquired later on the same day. After imaging studies, animals were sacrificed, and their liver excised for histology. Standardized Uptake Value (SUV) was calculated using a region of interest (ROI) placed on each tumor with focal uptake. Results: Acetate showed uptake in each HCC lesion when the animals were either fasted or fed with no significant difference in SUV values (p = 0.177);some of the tumors were histologically confirmed as well-differentiated HCC while others were confirmed as moderately- or poorly-differentiated HCC;no focal uptake was found in the control animal. For the accompanying FDG scans, the uptake was detected only in animals that were fasted although the uptake pattern was different from that with acetate. Conclusion: This study provided a hint that fasting or not has little impact on PET imaging of HCC with acetate. It also confirmed prior finding regarding tumor heterogeneity that led to different tracer uptake pattern in the same tumor. Human studies are needed to validate the findings from this pre-clinical investigation.展开更多
基金Supported by contract N01-AI-05399 to the College of Veterinary Medicine, Cornell University from the National Institute of Allergy and Infectious Diseases. PC and SM also have been supported by contract N01-AI-95390 to the Georgetown University Medical Center, Georgetown University from the National Institute of Allergy and Infectious Diseases
文摘This review describes the woodchuck and the woodchuck hepatitis virus (WHV) as an animal model for pathogenesis and therapy of chronic hepatitis B virus (HBV) infection and disease in humans. The establishment of woodchuck breeding colonies, and use of laboratory-reared woodchucks infected with defined WHV inocula, have enhanced our understanding of the virology and immunology of HBV infection and disease pathogenesis, including major sequelae like chronic hepatitis and hepatocellular carcinoma. The role of persistent WHV infection and of viral load on the natural history of infection and disease progression has been firmly established along the way. More recently, the model has shed new light on the role of host immune responses in these natural processes, and on how the immune system of the chronic carrier can be manipulated therapeutically to reduce or delay serious disease sequelae through induction of the recovery phenotype. The woodchuck is an outbred species and is not well defined immunologically due to a limitation of available host markers. However, the recent development of several key host response assays for woodchucks provides experimental opportunities for further mechanistic studies of outcome predictors in neonatal- and adult-acquired infections. Understanding the virological and immunological mechanisms responsible for resolution of self-limited infection, andfor the onset and maintenance of chronic infection, will greatly facilitate the development of successful strategies for the therapeutic eradication of established chronic HBV infection. Likewise, the results of drug efficacy and toxicity studies in the chronic carrier woodchucks are predictive for responses of patients chronically infected with HBV. Therefore, chronic WHV carrier woodchucks provide a well-characterized mammalian model for preclinical evaluation of the safety and efficacy of drug candidates, experimental therapeutic vaccines, and immunomodulators for the treatment and prevention of HBV disease sequelae.
基金an NIH grant CA095307 (Z. Lee, PI)by the Gene Expression Array Core Facility of the Comprehensive Cancer Center of Case Western Reserve University and University Hospitals of Cleveland, No. P30 CA43703
文摘AIM： To demonstrate the feasibility of using woodchuck samples on human microarrays, to provide insight into pathways involving positron emission tomography （PET） imaging tracers and to identify genes that could be potential molecular imaging targets for woodchuck hepatocellular carcinoma. METHODS： Labeled cRNA from woodchuck tissue samples were hybridized to Affymetrix U133 plus 2.0 GeneChips. Ten genes were selected for validation using quantitative RT-PCR and literature review was made. RESULTS： Testis enhanced gene transcript （BAX Inhibitor 1）, alpha-fetoprotein, isocitrate dehydrogenase 3 （NAD＋） beta, acetyI-CoA synthetase 2, carnitine palmitoyltransferase 2, and N-myc2 were up-regulated and spermidine/spermine N1-acetyltransferase was down-regulated in the woodchuck HCC. We also found previously published results supporting 8 of the 10 most up-regulated genes and all 10 of the 10 most downregulated genes. CONCLUSION： Many of our microarray results were validated using RT-PCR or literature search. Hence, we believe that woodchuck HCC and non-cancerous liver samples can be used on human microarrays to yield meaningful results.
文摘INTRODUCTIONHepatocellular carcinoma(HCC)is one of the major causes of death in the word.The mechanism of carcinogenesis is unknown,although it is widely accepted that HBV and HCV are clsely related to liver cancer[1-5[1-5].Previously,a variety of studies have described the differences in gene expression which distinguished tumor from nontumor[6-11].Cloning of the genes,especially the genes associated with HBV and HCV,is still very important to account for the development of liver cancer.
文摘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.
基金Deutsche Forschungsgemeinschaft (Lu 669/2-1, GRK1045/1, and Lu 669/5-1)
文摘The woodchuck model is an excellent animal model to study hepadnaviral infection. The new progresses in this model made possible to examine the T-cell mediated immune responses in acute and chronic hepadnaviral infection. Recently, a new assay for cytotoxic T-cells based on detection of CD107 was established for the woodchuck model. In addition, new immunotherapeutic approaches based on combination of potent antiviral treatment and DNA-protein vaccines were proven to be useful for treatment of chronic hepatitis B.
文摘The most commonly used preclinical models of hepatocellular carcinoma(HCC)are limited for use in testing of intra-arterial therapies such as transarterial chemoembolization and radioembolization.Issues encountered with the more commonly used animal models include dissimilarity in their disease development compared with humans and the size of the vasculature which can make intra-arterial therapy testing difficult or impossible.Here we describe the suitability of the woodchuck HCC model for testing of intra-arterial therapies.We describe the techniques for pre-embolization imaging assessment using CT and MRI,technical tips on performing angiography and embolization,and pathological assessment of treated liver.
基金supported by grants from the National Science and Technology Major Project for Infectious Diseases of China(No.2012ZX10004503)the National Natural Science Foundation of China(No.81101248,No.81261120397 and No.81371828)the Deutsche Forschungs-gemeinschaft(Transregio TRR60)
文摘Cytosolic retinoic acid-inducible gene I（RIG-I） is an important innate immune RNA sensor and can induce antiviral cytokines, e.g., interferon-β（IFN-β）. Innate immune response to hepatitis B virus（HBV） plays a pivotal role in viral clearance and persistence. However, knowledge of the role that RIG-I plays in HBV infection is limited. The woodchuck is a valuable model for studying HBV infection. To characterize the molecular basis of woodchuck RIG-I（w RIG-I）, we analyzed the complete coding sequences（CDSs） of w RIG-I, containing 2778 base pairs that encode 925 amino acids. The deduced w RIG-I protein was 106.847 k D with a theoretical isoelectric point（p I） of 6.07, and contained three important functional structures [caspase activation and recruitment domains（CARDs）, DEx D/H-box helicases, and a repressor domain（RD）]. In woodchuck fibroblastoma cell line（WH12/6）, w RIG-I-targeted small interfering RNA（si RNA） down-regulated RIG-I and its downstrean effector–IFN-β transcripts under RIG-I＇ ligand, 5＇-ppp double stranded RNA（ds RNA） stimulation. We also measured m RNA levels of w RIG-I in different tissues from healthy woodchucks and in the livers from woodchuck hepatitis virus（WHV）-infected woodchucks. The basal expression levels of w RIG-I were abundant in the kidney and liver. Importantly, w RIG-I was significantly up-regulated in acutely infected woodchuck livers, suggesting that RIG-I might be involved in WHV infection. These results may characterize RIG-I in the woodchuck model, providing a strong basis for further study on RIG-I-mediated innate immunity in HBV infection.
基金The studies were supported by operating grants MA-9256,MT-11262,RO-15174 and MOP-14818 from the Canadian Institutes of Health Researchformerly the Medical Research Council of Canada
文摘Woodchuck hepatitis virus (WHV) is molecularly and pathogenically closely related to hepatitis B virus (HBV).Both viruses display tropism towards hepatocytes and cells of the immune system and cause similar liver pathology,where acute hepatitis can progress to chronic hepatitis and to hepatocellular carcinoma (HCC).Two forms of occult hepadnaviral persistence were identified in the woodchuck-WHV model:secondary occult infection (SOI) and primary occult infection (POI).SOI occurs after resolution of a serologically apparent infection with hepatitis or after subclinical serologically evident virus exposure.POI is caused by small amounts of virus and progresses without serological infection markers,but the virus genome and its replication are detectable in the immune system and with time in the liver.SOI can be accompanied by minimal hepatitis,while the hallmark of POI is normal liver morphology.Nonetheless,HCC develops in about 20% of animals with SOI or POI within 3 to 5 years.The virus persists throughout the lifespan in both SOI and POI at serum levels rarely greater than 100 copies/mL,causes hepatitis and HCC when concentrated and administered to virus-na(i)ve woodchucks.SOI is accompanied by virusspecific T and B cell immune responses,while only virusspecific T cells are detected in POI.SOI coincides with protection against reinfection,while POI does not and hepatitis develops after challenge with liver pathogenic doses >1000 virions.Both SOI and POI are associated with virus DNA integration into the liver and the immune system genomes.Overall,SOI and POI are two distinct forms of silent hepadnaviral persistence that share common characteristics.Here,we review findings from the woodchuck model and discuss the relevant observations made in human occult HBV infection (OBI).
基金supported by the Chinese National Key Technology R&D Program(2015BAI09B06)the National Science and Technology Major Project for Infectious Diseases of China(2012ZX10004503,2017ZX10304402-002-005)the National Natural Science Foundation of China(81461130019)
文摘Even with an effective vaccine, an estimated 240 million people are chronically infected with hepatitis B virus （HBV） worldwide. Current antiviral therapies, including interferon and nucleot（s）ide analogues, rarely cure chronic hepatitis B. Animal models are very crucial for understanding the pathogenesis of chronic hepatitis B and developing new therapeutic drugs or strategies. HBV can only infect humans and chimpanzees, with the use of chimpanzees in HBV research strongly restricted. Thus, most advances in HBV research have been gained using mouse models with HBV replication or infection or models with HBV-related hepadnaviral infection. This review summarizes the animal models currently available for the study of HBV infection.
基金the Deutsche Forschungsgemeinschaft(TRR60 and GK 1045/2)National Major Science and Technology Project for Infectious Diseases of China(2008ZX10002-011,2012ZX10004503)+1 种基金the National Natural Science Foundation of China(No.30271170,30571646,81101248)the International Science&Technology CooperationProgram of China(2011DFA31030)for supporting some of the work in the review
文摘Chronic hepatitis B virus(CHB) is currently treated with either interferon-based or nucleot(s)idebased antiviral therapies.However,treatment with pegylated interferon alpha results in a durable antiviral response in only about 30%patients and is associated with side effects.Most patients receiving nucleot(s)ide analogue treatment do not establish long-term,durable control of Infection and have rebounding viremia after cessation of therapy.Thus,novel therapy strategies are necessary to achieve the induction of potent and durable antiviral immune responses of the patients which can maintain long-term control of viral replication.Therapeutic vaccination of HBV carriers is a promising strategy for the control of hepatitis B.Here the authors review new therapeutic vaccination strategies to treat chronic hepatitis B which may be introduced for patient treatment in the future.
文摘Chronic active hepatitis(CAH) is acknowledged as an imperative risk factor for the development of liver injury and hepatocellular carcinoma.The histological end points of CAH are chronic inflammation,fibrosis and cirrhosis which are coupled with increased DNA synthesis in cirrhotic vs healthy normal livers.The potential mechanism involved in CAH includes a combination of processes leading to liver cell necrosis,inflammation and cytokine production and liver scaring(fibrosis).The severity of liver damage is regulated by Hepatitis B virus genotypes and viral components.The viral and cellular factors that contribute to liver injury are discussed in this article.Liver injury caused by the viral infection affects many cellular processes such as cell signaling,apoptosis,transcription,DNA repair which in turn induce radical effects on cell survival,growth,transformation and maintenance.The consequence of such perturbations is resulted in the alteration of bile secretion,gluconeogenesis,glycolysis,detoxification and metabolism of carbohydrates,proteins,fat and balance of nutrients.The identification and elucidation of the molecular pathways perturbed by the viral proteins are important in order to design effective strategy to minimize and/or restore the hepatocytes injury.
基金supported in part by the Program for New Century Excellent Talents in University (Program No. NCET-12-0975)the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry+1 种基金Jiangsu Overseas research & training program for University Prominent Young and Middle-aged Teachers and Presidents (for Pinghu Zhang)Qinghai Province High-end Innovative Talent Thousand Talents Program (for Pinghu Zhang)
文摘2',3'-dideoxyguanosine(DoG) has been demonstrated to inhibit duck hepatitis B virus(DHBV) replication in vivo in a duck model of HBV infection. In the current study, the in vitro antiviral effects of DoG on human and animal hepadnaviruses were investigated. Our results showed that DoG effectively inhibited HBV, DHBV, and woodchuck hepatitis virus(WHV)replication in hepatocyte-derived cells in a dose-dependent manner, with 50% effective concentrations(EC50) of 0.3 ± 0.05, 6.82 ± 0.25, and 23.0 ± 1.5 lmol/L, respectively. Similar to other hepadnaviral DNA polymerase inhibitors,DoG did not alter the levels of intracellular viral RNA but induced the accumulation of a less-than-full-length viral RNA species, which was recently demonstrated to be generated by RNase H cleavage of pgRNA. Furthermore, using a transient transfection assay, DoG showed similar antiviral activity against HBV wild-type, 3TC-resistant rtA181 V, and adefovirresistant rtN236T mutants. Our results suggest that DoG has potential as a nucleoside analogue drug with anti-HBV activity.
文摘The clinical utility of positron emission tomography (PET) imaging for liver cancer applications is not clearly defined either for diagnosis or treatment assessment. Previous clinical studies demonstrated that fluorodeoxyglucose (FDG) did not show uptake in some hepatocellular carcinoma (HCC) while acetate showed uptake. Pre-imaging fasting is required for clinical PET imaging with FDG. No studies were done to confirm the effect of fasting on acetate uptake in HCC for PET imaging. We investigated this situation with a woodchuck model of viral infection-induced HCC. Methods: Four tumor-bearing and one control woodchucks were involved in this study. They were first imaged by PET in fed state followed by another imaging session one week later when they were fasted over-night. Some animals also had FDG- PET scan that was acquired later on the same day. After imaging studies, animals were sacrificed, and their liver excised for histology. Standardized Uptake Value (SUV) was calculated using a region of interest (ROI) placed on each tumor with focal uptake. Results: Acetate showed uptake in each HCC lesion when the animals were either fasted or fed with no significant difference in SUV values (p = 0.177);some of the tumors were histologically confirmed as well-differentiated HCC while others were confirmed as moderately- or poorly-differentiated HCC;no focal uptake was found in the control animal. For the accompanying FDG scans, the uptake was detected only in animals that were fasted although the uptake pattern was different from that with acetate. Conclusion: This study provided a hint that fasting or not has little impact on PET imaging of HCC with acetate. It also confirmed prior finding regarding tumor heterogeneity that led to different tracer uptake pattern in the same tumor. Human studies are needed to validate the findings from this pre-clinical investigation.
