Scientists discover key to hepatitis A virus replication, show drug effectiveness

The viral replication cycle is crucial for a virus to spread inside the body and cause disease. Focusing on that cycle in the hepatitis A virus (HAV), UNC School of Medicine scientists discovered that replication requires specific interactions between the human protein ZCCHC14 and a group of enzymes called TENT4 poly(A) polymerases. They also found that the oral compound RG7834 stopped replication at a key step, making it impossible for the virus to infect liver cells.

These findings, published in the Proceedings of the National Academy of Sciences, are the first to demonstrate an effective drug treatment against HAV in an animal model of the disease.

“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.

Lemon, who in the 1970s and 80s was part of a Walter Reed Army Medical Center research team that developed the first inactivated HAV vaccine administered to humans, said research on HAV tapered off after the vaccine became widely available in the mid-1990s. Cases plummeted in the 2000s as vaccination rates skyrocketed. Researchers turned their attention to hepatitis B and C viruses, both of which are very different from HAV and cause chronic disease. “It’s like comparing apples to turnips,” Lemon said. “The only similarity is that they all cause inflammation of the liver.” HAV is not even part of the same virus family as hepatitis B and C viruses.

Hepatitis A outbreaks have been on the rise since 2016, even though the HAV vaccine is very effective. Not everyone gets vaccinated, Lemon pointed out, and HAV can exist for long periods of time in the environment — such as on our hands and in food and water — resulting in more than 44,000 cases, 27,000 hospitalizations and 400 deaths in the United States since 2016, according to the CDC.

Several outbreaks have occurred over the past several years, including in San Diego in 2017 driven largely by homelessness and illicit drug use, causing severe illness in about 600 people and killing 20. In 2022, there was a small outbreak linked to organic strawberries in multiple states, leading to about a dozen hospitalizations. Another outbreak in 2019 was linked to fresh blackberries. Globally, tens of millions of HAV infections occur each year. Symptoms include fever, abdominal pain, jaundice, nausea, and loss of appetite and sense of taste. Once sick, there is no treatment.

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