title: Recapitulation of treatment response patterns in a novel humanized mouse model for chronic hepatitis B virus infection.
abstract: There are ~350 million chronic carriers of hepatitis B (HBV). While a prophylactic vaccine and drug regimens to suppress viremia are available, chronic HBV infection is rarely cured. HBV's limited host tropism leads to a scarcity of susceptible small animal models and is a hurdle to developing curative therapies. Mice that support engraftment with human hepatoctyes have traditionally been generated through crosses of murine liver injury models to immunodeficient backgrounds. Here, we describe the disruption of fumarylacetoacetate hydrolase directly in the NOD Rag1-/-IL2RγNULL (NRG) background using zinc finger nucleases. The resultant human liver chimeric mice sustain persistent HBV viremia for >90 days. When treated with standard of care therapy, HBV DNA levels decrease below detection but rebound when drug suppression is released, mimicking treatment response observed in patients. Our study highlights the utility of directed gene targeting approaches in zygotes to create new humanized mouse models for human diseases.
authors.affiliation: Department of Molecular Biology, Princeton University, 110 Lewis Thomas Laboratory, Washington Road, Princeton, New Jersey, NJ 08544, USA.
authors.forename: Benjamin Y
authors.initials: BY
authors.lastname: Winer
authors.affiliation: Department of Molecular Biology, Princeton University, 110 Lewis Thomas Laboratory, Washington Road, Princeton, New Jersey, NJ 08544, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Huang
authors.affiliation: Department of Technology Evaluation and Development, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609-1500 USA.
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Low
authors.affiliation: Department of Technology Evaluation and Development, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609-1500 USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Avery
authors.affiliation: Department of Molecular Biology, Princeton University, 110 Lewis Thomas Laboratory, Washington Road, Princeton, New Jersey, NJ 08544, USA.
authors.forename: Mihai-Alexandru
authors.initials: MA
authors.lastname: Pais
authors.affiliation: Department of Molecular Biology, Princeton University, 110 Lewis Thomas Laboratory, Washington Road, Princeton, New Jersey, NJ 08544, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Hrebikova
authors.affiliation: Department of Molecular Biology, Princeton University, 110 Lewis Thomas Laboratory, Washington Road, Princeton, New Jersey, NJ 08544, USA.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Siu
authors.affiliation: Department of Pathology, New York University Medical Center, New York, NY 10016, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Chiriboga
authors.affiliation: Department of Technology Evaluation and Development, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609-1500 USA.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Wiles
authors.affiliation: Department of Molecular Biology, Princeton University, 110 Lewis Thomas Laboratory, Washington Road, Princeton, New Jersey, NJ 08544, USA. Electronic address: aploss@princeton.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ploss
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005260:Female; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000821:virology; D022781:Hepatocytes / Q000821:virology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000821:virology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D018398:Homeodomain Proteins; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; C064658:RAG-1 protein
keywords: Antivirals; Genome engineering; Hepatitis B virus (HBV); Humanized mice