Title | Recapitulation of treatment response patterns in a novel humanized mouse model for chronic hepatitis B virus infection. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Winer, BY, Huang, T, Low, BE, Avery, C, Pais, M-A, Hrebikova, G, Siu, E, Chiriboga, L, Wiles, MV, Ploss, A |
Journal | Virology |
Volume | 502 |
Pagination | 63-72 |
Date Published | 2017 Feb |
ISSN | 1096-0341 |
Keywords | Animals, 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> |
DOI | 10.1016/j.virol.2016.12.017 |
Alternate Journal | Virology |
PubMed ID | 28006671 |
PubMed Central ID | PMC5414730 |
Grant List | P30 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 |