Characterization and Application of Precore/Core‐Related Antigens in Animal Models of Hepatitis B Virus Infection

Background and Aims The hepatitis B core‐related antigen (HBcrAg), a composite antigen of precore/core gene including classical hepatitis B core protein (HBc) and HBeAg and, additionally, the precore‐related antigen PreC, retaining the N‐terminal signal peptide, has emerged as a surrogate marker to...

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Vydané v:	Hepatology (Baltimore, Md.) Ročník 74; číslo 1; s. 99 - 115
Hlavní autori:	Hong, Xupeng, Luckenbaugh, Laurie, Perlman, David, Revill, Peter A., Wieland, Stefan F., Menne, Stephan, Hu, Jianming
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Wolters Kluwer Health, Inc 01.07.2021
Predmet:	Animal models Animals Antigen processing Antigens Antiviral drugs Biopsy Circular DNA Core protein DNA, Viral - isolation & purification Glycosylation Hepatitis B Hepatitis B - blood Hepatitis B - immunology Hepatitis B - virology Hepatitis B Core Antigens - blood Hepatitis B Core Antigens - immunology Hepatitis B Core Antigens - metabolism Hepatitis B e antigen Hepatitis B e Antigens - blood Hepatitis B e Antigens - immunology Hepatitis B e Antigens - metabolism Hepatitis B virus - genetics Hepatitis B virus - immunology Hepatitis B virus - isolation & purification Hepatitis B virus - pathogenicity Hepatitis B Virus, Woodchuck - genetics Hepatitis B Virus, Woodchuck - immunology Hepatitis B Virus, Woodchuck - isolation & purification Hepatitis B Virus, Woodchuck - pathogenicity Hepatology Liver - pathology Liver - virology Marmota Marmota monax Pan troglodytes Proteins Proteolysis Surface antigens Virions
ISSN:	0270-9139, 1527-3350, 1527-3350
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Abstract	Background and Aims The hepatitis B core‐related antigen (HBcrAg), a composite antigen of precore/core gene including classical hepatitis B core protein (HBc) and HBeAg and, additionally, the precore‐related antigen PreC, retaining the N‐terminal signal peptide, has emerged as a surrogate marker to monitor the intrahepatic HBV covalently closed circular DNA (cccDNA) and to define meaningful treatment endpoints. Approach and Results Here, we found that the woodchuck hepatitis virus (WHV) precore/core gene products (i.e., WHV core‐related antigen [WHcrAg]) include the WHV core protein and WHV e antigen (WHeAg) as well as the WHV PreC protein (WPreC) in infected woodchucks. Unlike in HBV infection, WHeAg and WPreC proteins were N‐glycosylated, and no significant amounts of WHV empty virions were detected in WHV‐infected woodchuck serum. WHeAg was the predominant form of WHcrAg, and a positive correlation was found between the serum WHeAg and intrahepatic cccDNA. Both WHeAg and WPreC antigens displayed heterogeneous proteolytic processing at their C‐termini, resulting in multiple species. Analysis of the kinetics of each component of the precore/core‐related antigen, along with serum viral DNA and surface antigens, in HBV‐infected chimpanzees and WHV‐infected woodchucks revealed multiple distinct phases of viral decline during natural resolution and in response to antiviral treatments. A positive correlation was found between HBc and intrahepatic cccDNA but not between HBeAg or HBcrAg and cccDNA in HBV‐infected chimpanzees, suggesting that HBc can be a better marker for intrahepatic cccDNA. Conclusions In conclusion, careful monitoring of each component of HBcrAg along with other classical markers will help understand intrahepatic viral activities to elucidate natural resolution mechanisms as well as guide antiviral development.
AbstractList	The hepatitis B core-related antigen (HBcrAg), a composite antigen of precore/core gene including classical hepatitis B core antigen (HBc) and e antigen (HBeAg), and additionally, the precore-related antigen PreC, retaining the N-terminal signal peptide, has emerged as a surrogate marker to monitor the intrahepatic hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) and to define new meaningful treatment endpoints. Here, we found that the woodchuck hepatitis virus (WHV) precore/core gene products (i.e., WHV core-related antigen, WHcrAg) include the WHV core protein (WHc), WHV e antigen (WHeAg), as well as the WHV PreC protein (WPreC) in infected woodchucks. Unlike in HBV infection, WHeAg and WPreC proteins were N-glycosylated, and no significant amounts of WHV empty virions were detected in WHV-infected woodchuck serum. WHeAg was the predominant form of WHcrAg, and a positive correlation was found between the serum WHeAg and intrahepatic cccDNA. Both WHeAg and WPreC antigens displayed heterogeneous proteolytic processing at their C-termini resulting in multiple species. Analysis of the kinetics of each component of the precore/core-related antigen, along with serum viral DNA and surface antigens, in HBV-infected chimpanzees and WHV-infected woodchucks revealed multiple distinct phases of viral decline during natural resolution and in response to antiviral treatments. A positive correlation was found between HBc and intrahepatic cccDNA, but not between HBeAg or HBcrAg and cccDNA in HBV-infected chimpanzees, suggesting that HBc can be a better marker for intrahepatic cccDNA. In conclusion, careful monitoring of each component of HBcrAg along with other classical markers will help understand intrahepatic viral activities to elucidate natural resolution mechanisms as well as guide antiviral development. The hepatitis B core-related antigen (HBcrAg), a composite antigen of precore/core gene including classical hepatitis B core protein (HBc) and HBeAg and, additionally, the precore-related antigen PreC, retaining the N-terminal signal peptide, has emerged as a surrogate marker to monitor the intrahepatic HBV covalently closed circular DNA (cccDNA) and to define meaningful treatment endpoints. Here, we found that the woodchuck hepatitis virus (WHV) precore/core gene products (i.e., WHV core-related antigen [WHcrAg]) include the WHV core protein and WHV e antigen (WHeAg) as well as the WHV PreC protein (WPreC) in infected woodchucks. Unlike in HBV infection, WHeAg and WPreC proteins were N-glycosylated, and no significant amounts of WHV empty virions were detected in WHV-infected woodchuck serum. WHeAg was the predominant form of WHcrAg, and a positive correlation was found between the serum WHeAg and intrahepatic cccDNA. Both WHeAg and WPreC antigens displayed heterogeneous proteolytic processing at their C-termini, resulting in multiple species. Analysis of the kinetics of each component of the precore/core-related antigen, along with serum viral DNA and surface antigens, in HBV-infected chimpanzees and WHV-infected woodchucks revealed multiple distinct phases of viral decline during natural resolution and in response to antiviral treatments. A positive correlation was found between HBc and intrahepatic cccDNA but not between HBeAg or HBcrAg and cccDNA in HBV-infected chimpanzees, suggesting that HBc can be a better marker for intrahepatic cccDNA. In conclusion, careful monitoring of each component of HBcrAg along with other classical markers will help understand intrahepatic viral activities to elucidate natural resolution mechanisms as well as guide antiviral development. The hepatitis B core-related antigen (HBcrAg), a composite antigen of precore/core gene including classical hepatitis B core protein (HBc) and HBeAg and, additionally, the precore-related antigen PreC, retaining the N-terminal signal peptide, has emerged as a surrogate marker to monitor the intrahepatic HBV covalently closed circular DNA (cccDNA) and to define meaningful treatment endpoints.BACKGROUND AND AIMSThe hepatitis B core-related antigen (HBcrAg), a composite antigen of precore/core gene including classical hepatitis B core protein (HBc) and HBeAg and, additionally, the precore-related antigen PreC, retaining the N-terminal signal peptide, has emerged as a surrogate marker to monitor the intrahepatic HBV covalently closed circular DNA (cccDNA) and to define meaningful treatment endpoints.Here, we found that the woodchuck hepatitis virus (WHV) precore/core gene products (i.e., WHV core-related antigen [WHcrAg]) include the WHV core protein and WHV e antigen (WHeAg) as well as the WHV PreC protein (WPreC) in infected woodchucks. Unlike in HBV infection, WHeAg and WPreC proteins were N-glycosylated, and no significant amounts of WHV empty virions were detected in WHV-infected woodchuck serum. WHeAg was the predominant form of WHcrAg, and a positive correlation was found between the serum WHeAg and intrahepatic cccDNA. Both WHeAg and WPreC antigens displayed heterogeneous proteolytic processing at their C-termini, resulting in multiple species. Analysis of the kinetics of each component of the precore/core-related antigen, along with serum viral DNA and surface antigens, in HBV-infected chimpanzees and WHV-infected woodchucks revealed multiple distinct phases of viral decline during natural resolution and in response to antiviral treatments. A positive correlation was found between HBc and intrahepatic cccDNA but not between HBeAg or HBcrAg and cccDNA in HBV-infected chimpanzees, suggesting that HBc can be a better marker for intrahepatic cccDNA.APPROACH AND RESULTSHere, we found that the woodchuck hepatitis virus (WHV) precore/core gene products (i.e., WHV core-related antigen [WHcrAg]) include the WHV core protein and WHV e antigen (WHeAg) as well as the WHV PreC protein (WPreC) in infected woodchucks. Unlike in HBV infection, WHeAg and WPreC proteins were N-glycosylated, and no significant amounts of WHV empty virions were detected in WHV-infected woodchuck serum. WHeAg was the predominant form of WHcrAg, and a positive correlation was found between the serum WHeAg and intrahepatic cccDNA. Both WHeAg and WPreC antigens displayed heterogeneous proteolytic processing at their C-termini, resulting in multiple species. Analysis of the kinetics of each component of the precore/core-related antigen, along with serum viral DNA and surface antigens, in HBV-infected chimpanzees and WHV-infected woodchucks revealed multiple distinct phases of viral decline during natural resolution and in response to antiviral treatments. A positive correlation was found between HBc and intrahepatic cccDNA but not between HBeAg or HBcrAg and cccDNA in HBV-infected chimpanzees, suggesting that HBc can be a better marker for intrahepatic cccDNA.In conclusion, careful monitoring of each component of HBcrAg along with other classical markers will help understand intrahepatic viral activities to elucidate natural resolution mechanisms as well as guide antiviral development.CONCLUSIONSIn conclusion, careful monitoring of each component of HBcrAg along with other classical markers will help understand intrahepatic viral activities to elucidate natural resolution mechanisms as well as guide antiviral development. Background and Aims The hepatitis B core‐related antigen (HBcrAg), a composite antigen of precore/core gene including classical hepatitis B core protein (HBc) and HBeAg and, additionally, the precore‐related antigen PreC, retaining the N‐terminal signal peptide, has emerged as a surrogate marker to monitor the intrahepatic HBV covalently closed circular DNA (cccDNA) and to define meaningful treatment endpoints. Approach and Results Here, we found that the woodchuck hepatitis virus (WHV) precore/core gene products (i.e., WHV core‐related antigen [WHcrAg]) include the WHV core protein and WHV e antigen (WHeAg) as well as the WHV PreC protein (WPreC) in infected woodchucks. Unlike in HBV infection, WHeAg and WPreC proteins were N‐glycosylated, and no significant amounts of WHV empty virions were detected in WHV‐infected woodchuck serum. WHeAg was the predominant form of WHcrAg, and a positive correlation was found between the serum WHeAg and intrahepatic cccDNA. Both WHeAg and WPreC antigens displayed heterogeneous proteolytic processing at their C‐termini, resulting in multiple species. Analysis of the kinetics of each component of the precore/core‐related antigen, along with serum viral DNA and surface antigens, in HBV‐infected chimpanzees and WHV‐infected woodchucks revealed multiple distinct phases of viral decline during natural resolution and in response to antiviral treatments. A positive correlation was found between HBc and intrahepatic cccDNA but not between HBeAg or HBcrAg and cccDNA in HBV‐infected chimpanzees, suggesting that HBc can be a better marker for intrahepatic cccDNA. Conclusions In conclusion, careful monitoring of each component of HBcrAg along with other classical markers will help understand intrahepatic viral activities to elucidate natural resolution mechanisms as well as guide antiviral development. Background and AimsThe hepatitis B core‐related antigen (HBcrAg), a composite antigen of precore/core gene including classical hepatitis B core protein (HBc) and HBeAg and, additionally, the precore‐related antigen PreC, retaining the N‐terminal signal peptide, has emerged as a surrogate marker to monitor the intrahepatic HBV covalently closed circular DNA (cccDNA) and to define meaningful treatment endpoints.Approach and ResultsHere, we found that the woodchuck hepatitis virus (WHV) precore/core gene products (i.e., WHV core‐related antigen [WHcrAg]) include the WHV core protein and WHV e antigen (WHeAg) as well as the WHV PreC protein (WPreC) in infected woodchucks. Unlike in HBV infection, WHeAg and WPreC proteins were N‐glycosylated, and no significant amounts of WHV empty virions were detected in WHV‐infected woodchuck serum. WHeAg was the predominant form of WHcrAg, and a positive correlation was found between the serum WHeAg and intrahepatic cccDNA. Both WHeAg and WPreC antigens displayed heterogeneous proteolytic processing at their C‐termini, resulting in multiple species. Analysis of the kinetics of each component of the precore/core‐related antigen, along with serum viral DNA and surface antigens, in HBV‐infected chimpanzees and WHV‐infected woodchucks revealed multiple distinct phases of viral decline during natural resolution and in response to antiviral treatments. A positive correlation was found between HBc and intrahepatic cccDNA but not between HBeAg or HBcrAg and cccDNA in HBV‐infected chimpanzees, suggesting that HBc can be a better marker for intrahepatic cccDNA.ConclusionsIn conclusion, careful monitoring of each component of HBcrAg along with other classical markers will help understand intrahepatic viral activities to elucidate natural resolution mechanisms as well as guide antiviral development.
Author	Perlman, David Hu, Jianming Menne, Stephan Luckenbaugh, Laurie Hong, Xupeng Revill, Peter A. Wieland, Stefan F.
AuthorAffiliation	2. Merck Research Labs Exploratory Sciences Center, Cambridge, MA, USA 5. Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, District of Columbia, USA 1. Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA, USA 3. Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia 4. Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
AuthorAffiliation_xml	– name: 1. Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA, USA – name: 3. Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia – name: 5. Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, District of Columbia, USA – name: 4. Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland – name: 2. Merck Research Labs Exploratory Sciences Center, Cambridge, MA, USA
Author_xml	– sequence: 1 givenname: Xupeng surname: Hong fullname: Hong, Xupeng organization: The Pennsylvania State University College of Medicine – sequence: 2 givenname: Laurie surname: Luckenbaugh fullname: Luckenbaugh, Laurie organization: The Pennsylvania State University College of Medicine – sequence: 3 givenname: David surname: Perlman fullname: Perlman, David organization: Merck Research Labs Exploratory Sciences Center – sequence: 4 givenname: Peter A. surname: Revill fullname: Revill, Peter A. organization: Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity – sequence: 5 givenname: Stefan F. surname: Wieland fullname: Wieland, Stefan F. organization: University of Basel – sequence: 6 givenname: Stephan surname: Menne fullname: Menne, Stephan organization: Georgetown University Medical Center – sequence: 7 givenname: Jianming surname: Hu fullname: Hu, Jianming email: juh13@psu.edu organization: The Pennsylvania State University College of Medicine
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Writing-original draft: X.Hong, J.Hu Writing-review & editing: X.Hong, L.Luckenbaugh, D.Perlman, P.A.Revill, S.F.Wieland, S.Menne, J.Hu Conceptualization: X.Hong, J.Hu Funding acquisition: J.Hu Resources: P.A.Revill, S.F.Wieland, S.Menne, J.Hu Formal Analysis: X.Hong, J.Hu Methodology: X.Hong, L.Luckenbaugh, D.Perlman Project administration: J.Hu Data curation: X.Hong, L.Luckenbaugh, D.Perlman, S.F.Wieland, S.Menne Supervision: J.Hu Author Contributions
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Snippet	Background and Aims The hepatitis B core‐related antigen (HBcrAg), a composite antigen of precore/core gene including classical hepatitis B core protein (HBc)... The hepatitis B core-related antigen (HBcrAg), a composite antigen of precore/core gene including classical hepatitis B core protein (HBc) and HBeAg and,... Background and AimsThe hepatitis B core‐related antigen (HBcrAg), a composite antigen of precore/core gene including classical hepatitis B core protein (HBc)... The hepatitis B core-related antigen (HBcrAg), a composite antigen of precore/core gene including classical hepatitis B core antigen (HBc) and e antigen...
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SubjectTerms	Animal models Animals Antigen processing Antigens Antiviral drugs Biopsy Circular DNA Core protein DNA, Viral - isolation & purification Glycosylation Hepatitis B Hepatitis B - blood Hepatitis B - immunology Hepatitis B - virology Hepatitis B Core Antigens - blood Hepatitis B Core Antigens - immunology Hepatitis B Core Antigens - metabolism Hepatitis B e antigen Hepatitis B e Antigens - blood Hepatitis B e Antigens - immunology Hepatitis B e Antigens - metabolism Hepatitis B virus - genetics Hepatitis B virus - immunology Hepatitis B virus - isolation & purification Hepatitis B virus - pathogenicity Hepatitis B Virus, Woodchuck - genetics Hepatitis B Virus, Woodchuck - immunology Hepatitis B Virus, Woodchuck - isolation & purification Hepatitis B Virus, Woodchuck - pathogenicity Hepatology Liver - pathology Liver - virology Marmota Marmota monax Pan troglodytes Proteins Proteolysis Surface antigens Virions
Title	Characterization and Application of Precore/Core‐Related Antigens in Animal Models of Hepatitis B Virus Infection
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