Liver-Humanized NSG-PiZ Mice Support the Study of Chronic Hepatitis B Virus Infection and Antiviral Therapies
ABSTRACT Hepatitis B virus (HBV) is a pathogen of major public health importance that is largely incurable once a chronic infection is established. Only humans and great apes are fully permissive to HBV infection, and this species restriction has impacted HBV research by limiting the utility of smal...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2023-06-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.05176-22 |
| _version_ | 1827925118944280576 |
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| author | Rossana Colón-Thillet Daniel Stone Michelle A. Loprieno Lindsay Klouser Pavitra Roychoudhury Tracy K. Santo Hong Xie Laurence Stensland Sarah L. Upham Gregory Pepper Meei-Li Huang Martine Aubert Keith R. Jerome |
| author_facet | Rossana Colón-Thillet Daniel Stone Michelle A. Loprieno Lindsay Klouser Pavitra Roychoudhury Tracy K. Santo Hong Xie Laurence Stensland Sarah L. Upham Gregory Pepper Meei-Li Huang Martine Aubert Keith R. Jerome |
| author_sort | Rossana Colón-Thillet |
| collection | DOAJ |
| description | ABSTRACT Hepatitis B virus (HBV) is a pathogen of major public health importance that is largely incurable once a chronic infection is established. Only humans and great apes are fully permissive to HBV infection, and this species restriction has impacted HBV research by limiting the utility of small animal models. To combat HBV species restrictions and enable more in vivo studies, liver-humanized mouse models have been developed that are permissive to HBV infection and replication. Unfortunately, these models can be difficult to establish and are expensive commercially, which has limited their academic use. As an alternative mouse model to study HBV, we evaluated liver-humanized NSG-PiZ mice and showed that they are fully permissive to HBV. HBV selectively replicates in human hepatocytes within chimeric livers, and HBV-positive (HBV+) mice secrete infectious virions and hepatitis B surface antigen (HBsAg) into blood while also harboring covalently closed circular DNA (cccDNA). HBV+ mice develop chronic infections lasting at least 169 days, which should enable the study of new curative therapies targeting chronic HBV, and respond to entecavir therapy. Furthermore, HBV+ human hepatocytes in NSG-PiZ mice can be transduced by AAV3b and AAV.LK03 vectors, which should enable the study of gene therapies that target HBV. In summary, our data demonstrate that liver-humanized NSG-PiZ mice can be used as a robust and cost-effective alternative to existing chronic hepatitis B (CHB) models and may enable more academic research labs to study HBV disease pathogenesis and antiviral therapy. IMPORTANCE Liver-humanized mouse models have become the gold standard for the in vivo study of hepatitis B virus (HBV), yet their complexity and cost have prohibited widespread use of existing models in research. Here, we show that the NSG-PiZ liver-humanized mouse model, which is relatively inexpensive and simple to establish, can support chronic HBV infection. Infected mice are fully permissive to hepatitis B, supporting both active replication and spread, and can be used to study novel antiviral therapies. This model is a viable and cost-effective alternative to other liver-humanized mouse models that are used to study HBV. |
| first_indexed | 2024-03-13T05:20:36Z |
| format | Article |
| id | doaj.art-dbccde519db843748d5b366653d72100 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-03-13T05:20:36Z |
| publishDate | 2023-06-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-dbccde519db843748d5b366653d721002023-06-15T13:18:33ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972023-06-0111310.1128/spectrum.05176-22Liver-Humanized NSG-PiZ Mice Support the Study of Chronic Hepatitis B Virus Infection and Antiviral TherapiesRossana Colón-Thillet0Daniel Stone1Michelle A. Loprieno2Lindsay Klouser3Pavitra Roychoudhury4Tracy K. Santo5Hong Xie6Laurence Stensland7Sarah L. Upham8Gregory Pepper9Meei-Li Huang10Martine Aubert11Keith R. Jerome12Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USADepartment of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USADepartment of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USADepartment of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USADepartment of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USADepartment of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USADepartment of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USAABSTRACT Hepatitis B virus (HBV) is a pathogen of major public health importance that is largely incurable once a chronic infection is established. Only humans and great apes are fully permissive to HBV infection, and this species restriction has impacted HBV research by limiting the utility of small animal models. To combat HBV species restrictions and enable more in vivo studies, liver-humanized mouse models have been developed that are permissive to HBV infection and replication. Unfortunately, these models can be difficult to establish and are expensive commercially, which has limited their academic use. As an alternative mouse model to study HBV, we evaluated liver-humanized NSG-PiZ mice and showed that they are fully permissive to HBV. HBV selectively replicates in human hepatocytes within chimeric livers, and HBV-positive (HBV+) mice secrete infectious virions and hepatitis B surface antigen (HBsAg) into blood while also harboring covalently closed circular DNA (cccDNA). HBV+ mice develop chronic infections lasting at least 169 days, which should enable the study of new curative therapies targeting chronic HBV, and respond to entecavir therapy. Furthermore, HBV+ human hepatocytes in NSG-PiZ mice can be transduced by AAV3b and AAV.LK03 vectors, which should enable the study of gene therapies that target HBV. In summary, our data demonstrate that liver-humanized NSG-PiZ mice can be used as a robust and cost-effective alternative to existing chronic hepatitis B (CHB) models and may enable more academic research labs to study HBV disease pathogenesis and antiviral therapy. IMPORTANCE Liver-humanized mouse models have become the gold standard for the in vivo study of hepatitis B virus (HBV), yet their complexity and cost have prohibited widespread use of existing models in research. Here, we show that the NSG-PiZ liver-humanized mouse model, which is relatively inexpensive and simple to establish, can support chronic HBV infection. Infected mice are fully permissive to hepatitis B, supporting both active replication and spread, and can be used to study novel antiviral therapies. This model is a viable and cost-effective alternative to other liver-humanized mouse models that are used to study HBV.https://journals.asm.org/doi/10.1128/spectrum.05176-22hepatitis B virusengraftmentcccDNAhepatocyteadeno-associated virusRTi |
| spellingShingle | Rossana Colón-Thillet Daniel Stone Michelle A. Loprieno Lindsay Klouser Pavitra Roychoudhury Tracy K. Santo Hong Xie Laurence Stensland Sarah L. Upham Gregory Pepper Meei-Li Huang Martine Aubert Keith R. Jerome Liver-Humanized NSG-PiZ Mice Support the Study of Chronic Hepatitis B Virus Infection and Antiviral Therapies Microbiology Spectrum hepatitis B virus engraftment cccDNA hepatocyte adeno-associated virus RTi |
| title | Liver-Humanized NSG-PiZ Mice Support the Study of Chronic Hepatitis B Virus Infection and Antiviral Therapies |
| title_full | Liver-Humanized NSG-PiZ Mice Support the Study of Chronic Hepatitis B Virus Infection and Antiviral Therapies |
| title_fullStr | Liver-Humanized NSG-PiZ Mice Support the Study of Chronic Hepatitis B Virus Infection and Antiviral Therapies |
| title_full_unstemmed | Liver-Humanized NSG-PiZ Mice Support the Study of Chronic Hepatitis B Virus Infection and Antiviral Therapies |
| title_short | Liver-Humanized NSG-PiZ Mice Support the Study of Chronic Hepatitis B Virus Infection and Antiviral Therapies |
| title_sort | liver humanized nsg piz mice support the study of chronic hepatitis b virus infection and antiviral therapies |
| topic | hepatitis B virus engraftment cccDNA hepatocyte adeno-associated virus RTi |
| url | https://journals.asm.org/doi/10.1128/spectrum.05176-22 |
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