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Virology. 2017 Feb;502:63-72. doi: 10.1016/j.virol.2016.12.017. Epub 2016 Dec 19.

Recapitulation of treatment response patterns in a novel humanized mouse model for chronic hepatitis B virus infection.

Author information

1
Department of Molecular Biology, Princeton University, 110 Lewis Thomas Laboratory, Washington Road, Princeton, New Jersey, NJ 08544, USA.
2
Department of Technology Evaluation and Development, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609-1500 USA.
3
Department of Pathology, New York University Medical Center, New York, NY 10016, USA.
4
Department of Molecular Biology, Princeton University, 110 Lewis Thomas Laboratory, Washington Road, Princeton, New Jersey, NJ 08544, USA. Electronic address: aploss@princeton.edu.

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.

KEYWORDS:

Antivirals; Genome engineering; Hepatitis B virus (HBV); Humanized mice

PMID:
28006671
PMCID:
PMC5414730
DOI:
10.1016/j.virol.2016.12.017
[Indexed for MEDLINE]
Free PMC Article

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