Journal
VIROLOGY
Volume 502, Issue -, Pages 63-72Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.virol.2016.12.017
Keywords
Hepatitis B virus (HBV); Humanized mice; Antivirals; Genome engineering
Categories
Funding
- National Institutes of Health [R01 AI079031, R01 AI107301, R21AI117213]
- American Cancer Society [RSG-15-048-01-MPC]
- Burroughs Wellcome Fund Award [1015389]
- Global Health Fund of Princeton University
- Laura and Isaac Perlmutter Cancer Center
- National Institutes of Health S10 Grants
- NIAID
- Evangelisches Studienwerk Villigst
- NIH/NCI [P30CA016087]
- NIH/ORIP [S10OD01058, S10OD018338]
- Jackson Laboratory
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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(-/-) IL2R gamma NULL (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.
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