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Key Step in Hepatitis A Virus Replication and Potential Drug for Its Targeting Identified

Researchers at the University of North Carolina School of Medicine have discovered the mechanism by which hepatitis A virus replicates and have successfully identified a drug that has the capability to stop such replications.

For a virus to spread in the body to cause infection, it has to replicate. A team of scientists from the University of North Carolina Health School of Medicine has found that TENT4 poly(A) polymerases are essential for the replication process of Hepatitis A viruses (HAV) and have also discovered an orally administered synthetic compound that is capable of inhibiting a key step of the replication process, rendering it impossible for the virus to infect liver cells.

Their research was published in the Proceedings of the National Academy of Sciences and is the first study to describe a successful drug treatment of HAV in animal models.

“Our research demonstrates that targeting this protein complex with an orally delivered, small-molecule therapeutic halts viral replication and reverses liver inflammation in a mouse model of hepatitis A, providing proof-of-principle for antiviral therapy and the means to stop the spread of hepatitis A in outbreak settings,” said senior author Stanley M. Lemon, MD, professor in the UNC Department of Medicine and UNC Department of Microbiology & Immunology, and member of the UNC Institute for Global Health and Infectious Diseases.

Professor Lemon has been involved in Hepatitis A virus (HAV) research since the 1970s and was part of the original Walter Reed Army Medical Center team that developed the first HAV vaccines that were approved for human use. Since that breakthrough, research interests in Hepatitis A have diminished, but a new threat looms on the horizon as Hepatitis A outbreaks have been steadily growing in size since 2016, despite the effectiveness of the existing Hepatitis A vaccine. This may be due to the increasing anti-vaccine sentiments in the population and coupled with the prevalence of HAV in the environment and its ability to withstand environmental stresses, HAV has caused around 27,000 hospitalisations and 400 deaths in the United States since 2016, in line with data collected by the Centers for Disease Control and Prevention.

Across the globe, millions of Hepatitis A infections occur each year. Common symptoms include abdominal pain, fever, jaundice, nausea, a loss of appetite, and a sense of taste. It is also currently incurable.

However, Professor Lemon and his team discovered how the hepatitis A virus adapts itself to the environment in the human liver in 2013. The virus steals fragments of liver cell membranes as it leaves them, allowing it to “disguise” itself and avoid detection from antibodies that would otherwise kill it and prevent its spread through the bloodstream.

In recent years, other research has indicated that the Hepatitis B virus, a close cousin of the Hepatitis A virus, requires TENT4A/B for its replication. At the same time, Professor Lemon’s team was also trying to identify key human proteins required by HAV for replication and successfully managed to identify ZCCHC14, a unique protein that interacts favourably with zinc and binds to RNA.

“This was the tipping point for this current study,” Lemon said. “We found ZCCHC14 binds very specifically to a certain part of HAV’s RNA, the molecule that contains the virus’s genetic information. And because of that binding, the virus is able to recruit TENT4 from the human cell.”

TENT-4 is used by the human body in RNA modification processes required by cell growth. HAV makes use of this protein to replicate its own genome and produce more copies of itself.

Having identified the inhibition of TENT-4 recruitment as a potential therapeutic target for the spread of HAV, the team of researchers introduced the compound RG7834, which had been found to protect against the infection by Hepatitis B viruses in prior research by stopping the virus’ TENT-4 recruitment. They found that the RG7834 compound reduced the virus’ ability to damage the liver to a large extent in mice models that had been genetically engineered to develop Hepatitis A infection. The dose of the compound was verified to be safe for the mice in the experiment given the design of the study.

“This compound is a long way from human use,” Lemon said, “But it points the path to an effective way to treat a disease for which we have no treatment at all.”

In previous research, Hoffmann-La Roche had tested RG7834 in humans in a phase 1 trial to treat chronic Hepatitis B disease, but the studies with animal models suggested its long-term toxicity.

“The treatment for Hepatitis A would be short term,” Lemon said, “and, more importantly, our group and others are working on compounds that would hit the same target without toxic effects.” [APBN]

Source: Li et al. (2022). The ZCCHC14/TENT4 complex is required for hepatitis A virus RNA synthesis. Proceedings of the National Academy of Sciences, 119(28), e2204511119.