New Research Tool for Hepatitis B Developed by Rockefeller University Scientists


Charles Rice’s work led to the development of antiviral cures of hepatitis C. Now his lab is turning to hepatitis B and a technique that uses pregenomic RNA.

A little more than a quarter of a century ago, virologist Charles M. Rice, Ph.D., pioneered a technique that eventually led to the development of the antiviral that cures 95% of patients infected with hepatitis C (HCV). That research won Rice a share of the 2020 Nobel Prize in Physiology or Medicine.

Now scientists from Rice’s Rockefeller University lab have developed “a unique and versatile tool” for studying hepatitis B biology that might stimulate research into treatment for that kind of hepatitis. The research paper outlining the tool was published in Science Advances in April.

Here “we demonstrate that initiating HBV replication in vitro-transcribed pgRNA (pregenomic RNA) can be used to study post-entry steps in the HBV life cycle with excellent signal-to-noise properties,” the research team writes. “These properties, for the first time in cell culture, enable identification of sequence variants that confer resistance to anti-HBV drugs.”

The researchers said their research was inspired by previous work with duck hepatitis B virus and experiments that showed its pregenomic RNA can start infection in cultured cells.

Approximately 1.2 million people in the United States have HBV and about 350 million worldwide, according to the Centers for Disease Control and Prevention.

HBV is usually asymptomatic until liver disease has progressed and is untreatable. An effective vaccine has been available since 1980.

But current antiviral therapies for HBV can suppress the virus but often cause serious side effects and are largely ineffective. Moreover, many of the people with HBV cannot access consistent therapy, according to the WHO.

“Standard therapies for chronic HBV injectable interferon and orally administered nucleot(s)ide analogs,” according to the research paper. “Therapy can result in functional cure in 10% of patients, but it often elicits intolerable side effects, and since few patients benefit, it is seldom used.”

HCV and HBV attack the liver. Both are easily transmittable and hard to cure. But they are otherwise different viruses. HCV is an RNA virus and HBV is a DNA virus, with a unique structure that, until now, has been challenging to study in the lab, Bill Schneider, a research associate in Rice’s lab and co-author of the paper, told the university’s online publication.

Interest in finding a cure for HBV was renewed in 2012 after the discovery of the HBV entry receptor which made it possible to study the virus’s full lifecycle. But existing cell culture-based methods still had several limitations that hampered progress. Foremost among those limitations, according to the research paper, was eliminating “contaminating background signals” from input virus or plasmid DNA.

The Rice’s lab researchers developed a method that can be used to study post-entry steps in the HBV life-cycle with “excellent signal-to-noise properties.” The breakthrough, the researchers write, will allow scientists to screen thousands of HBV sequence variants at once and gain insights into the virus’s drug resistant mechanisms and prioritize potential variants of interest or concern.

“Together, this platform has a unique place in drug development pipelines and great potential to facilitate the discovery of HBV biology,” the paper concludes.

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