Genetically humanized mice could boost fight against aggressive hepatitis

June 27, 2018, Princeton University

Hepatitis delta virus (HDV) causes the most aggressive form of viral hepatitis in humans, putting at least 20 million people worldwide at risk of developing liver fibrosis, cirrhosis, and liver cancer. Efforts to develop effective treatments against HDV have been hampered by the fact that laboratory mice are not susceptible to the virus. But, in a study published June 27, 2018, in the journal Science Translational Medicine, Alexander Ploss and colleagues describe a genetically humanized mouse that can be persistently infected with HDV.

HDV is a small, RNA-based "satellite" virus that produces just a single protein of its own and therefore requires additional proteins provided by another virus, hepatitis B virus (HBV). HDV can infect patients already carrying HBV, or both viruses can infect patients simultaneously. Though infections can be prevented with an anti-HBV vaccine, there are no antiviral therapies available to cure existing HDV infections.

HDV and HBV infect the liver by binding to a protein called NTCP that is present on the surface of . But the viruses only recognize the version of NTCP present in humans and a few other primates, and therefore can't infect mice or other small mammals that produce their own versions of NTCP. This has made it difficult to study HBV and HDV infections in the laboratory. Researchers have tried transplanting human liver cells into immunocompromised mice before infecting them with , but this approach has produced inconsistent results and is both expensive and time-consuming.

Ploss and colleagues, led by graduate student Benjamin Winer, took a different approach. They generated mice that express the human NTCP protein in their liver cells, allowing these cells to be infected by HBV and HDV.

In these mice, HBV failed to replicate after entering mouse liver cells but HDV was able to establish persistent infection when provided with the HBV proteins it needs to propagate. For example, mice genetically engineered to produce both human NTCP and the entire HBV genome could be infected with HDV for up to 14 days. "To our knowledge, this is the first time the entire HDV life cycle has been recapitulated in a mouse model with inheritable susceptibility to HDV," Ploss said.

The mice were able to rid themselves of HDV before they developed any liver damage, apparently by mounting an immune response involving antiviral interferon proteins and various white blood cell types, including Natural Killer (NK) cells and T cells. Accordingly, mice expressing human NTCP and the HBV genome, but lacking functional B, T, and NK could be infected with HDV for two months or more.

These immunocompromised animals allowed Ploss and colleagues to test the effectiveness of two drugs that are currently being developed as treatments for HDV infection. Both drugs—either alone or in combination—suppressed the levels of HDV in immunocompromised mice after viral infection. But the drugs were not able to completely clear the of HDV; viral levels rose again within weeks of stopping treatment.

"This is largely in line with recently reported data from clinical trials, showing the utility of our model for preclinical antiviral drug testing," Winer said.

"Our model is amenable to genetic manipulations, robust, and can be adopted as a method to rapidly screen for potential treatments," Ploss added.

Timothy M. Block, president of the Hepatitis B Foundation and its Baruch S. Blumberg Institute, who was not involved in the study, said "These systems should be able to provide practical, and presumably economical tools. Their work is urgently needed, and a desperate community welcomes it. I emphasize that it is often the new methods in science that revolutionize a field such as drug discovery, almost as much as the new drugs themselves."

Explore further: New mouse model for hepatitis C

More information: B.Y. Winer el al., "Preclinical assessment of antiviral combination therapy in a genetically humanized mouse model for hepatitis delta virus infection," Science Translational Medicine (2018). stm.sciencemag.org/lookup/doi/ … scitranslmed.aap9328

Related Stories

New mouse model for hepatitis C

September 19, 2013
Hepatitis C affects about three million people in the U.S. and is a leading cause of chronic liver disease, so creating a vaccine and new treatments is an important public health goal. Most research to date has been done ...

Researchers report new system to study chronic hepatitis B

July 25, 2017
Scientists from Princeton University's Department of Molecular Biology have successfully tested a cell-culture system that will allow researchers to perform laboratory-based studies of long-term hepatitis B virus (HBV) infections. ...

Scientists uncover a factor important for Zika virus host species restriction

June 19, 2018
Princeton University researchers Qiang Ding, Alexander Ploss, and colleagues have identified one of the mechanisms by which Zika virus (ZIKV) circumvents immune control to replicate in human cells. The paper detailing this ...

Scientists create first genetically humanized mouse model for hepatitis C

June 8, 2011
Scientists at Rockefeller University and The Scripps Research Institute have developed the first genetically humanized mouse model for hepatitis C, an achievement that will enable researchers to test molecules that block ...

New model for hepatitis B helps identify potential new therapeutic approach

October 26, 2015
A promising new avenue for treating hepatitis B has been reported by researchers at Hiroshima University who have developed a new animal model of the disease.

Recommended for you

Scientists uncover DNA 'shield' with crucial roles in normal cell division

July 18, 2018
Scientists have made a major discovery about how cells repair broken strands of DNA that could have huge implications for the treatment of cancer.

Researchers develop novel bioengineering technique for personalized bone grafts

July 18, 2018
Scientists from the New York Stem Cell Foundation (NYSCF) Research Institute have developed a new bone engineering technique called Segmental Additive Tissue Engineering (SATE). The technique, described in a paper published ...

Researchers report protein kinase as the switch controlling obesity and diabetes

July 18, 2018
One of the research lines targeting the worldwide obesity epidemic is the manipulation of brown adipose tissue, a 'good' type of fat that burns lipids to maintain an appropriate body temperature. Researchers at the Centro ...

New retinal ganglion cell subtypes emerge from single-cell RNA sequencing

July 18, 2018
Single-cell sequencing technologies are filling in fine details in the catalog of life. Researchers at the University of Connecticut Health Center (UConn Health) and The Jackson Laboratory (JAX) have identified 40 subtypes ...

Scientists find malformations and lower survival rates in zebrafish embryos exposed to cannabinoids

July 16, 2018
Exposure to the main chemical components of cannabis has a detrimental effects on developing zebrafish embryos, according to a new study conducted by University of Alberta biologists.

Fetal gene therapy prevents fatal neurodegenerative disease

July 16, 2018
A fatal neurodegenerative condition known as Gaucher disease can be prevented in mice following fetal gene therapy, finds a new study led by UCL, the KK Women's and Children's Hospital and National University Health System ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.