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

TitleRecapitulation of treatment response patterns in a novel humanized mouse model for chronic hepatitis B virus infection.
Publication TypeJournal Article
Year of Publication2017
AuthorsWiner, BY, Huang, T, Low, BE, Avery, C, Pais, M-A, Hrebikova, G, Siu, E, Chiriboga, L, Wiles, MV, Ploss, A
JournalVirology
Volume502
Pagination63-72
Date Published2017 02
ISSN1096-0341
KeywordsAnimals, Antiviral Agents, Disease Models, Animal, Female, Hepatitis B virus, Hepatitis B, Chronic, Hepatocytes, Homeodomain Proteins, Humans, Interleukin Receptor Common gamma Subunit, Liver, Male, Mice, Mice, Inbred NOD, Mice, Knockout, Virus Replication
Abstract

<p>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.</p>

DOI10.1016/j.virol.2016.12.017
Alternate JournalVirology
PubMed ID28006671
PubMed Central IDPMC5414730
Grant ListP30 CA016087 / CA / NCI NIH HHS / United States
P30 CA034196 / CA / NCI NIH HHS / United States
S10 OD018338 / OD / NIH HHS / United States
R01 AI079031 / AI / NIAID NIH HHS / United States
R21 AI117213 / AI / NIAID NIH HHS / United States
F31 AI122480 / AI / NIAID NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States
R01 AI107301 / AI / NIAID NIH HHS / United States