The viral replication cycle is crucial for a virus to spread through the body and cause disease. Focusing on that cycle in the hepatitis A virus (HAV), scientists at the University of North Carolina (USA) have found that replication requires specific interactions between the human protein ZCCHC14 and a group of enzymes called TENT4 poly(A) polymerases.
They have also found that the oral compound RG7834 stopped replication at a key step, making it impossible for the virus to infect liver cells, as published in the journal ‘Proceedings of the National Academy of Sciences’.
These results are the first to demonstrate an effective pharmacological treatment against HAV in an animal model of the disease.
“Our research demonstrates that treatment of this protein complex with an orally administered small molecule therapeutic stops virus 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 outbreaks,” explains lead author Stanley M. Lemon, a professor in the Department of Medicine and the Department of Microbiology and Immunology of the UNCand a member of the UNC Institute for Global Health and Infectious Diseases.
Inactivated vaccine against HAV
Lemon, who in the 1970s and 1980s was part of a research team at Walter Reed Army Medical Center that developed the first inactivated HAV vaccine administered to humans, notes that HAV research declined after the vaccine became widely available in the mid-1990s. Cases plummeted in the 2000s as vaccination rates soared.
The researchers focused their attention on hepatitis B and C viruses, which are very different from HAV and cause chronic diseases. The only similarity is that they all cause inflammation of the liver.” HAV is not even part of the same family of viruses as hepatitis B and C.
Hepatitis A outbreaks have increased since 2016, despite the highly effective HAV vaccine. Not everyone gets vaccinated, Lemon notes, and HAV can exist for long periods of time in the environment, such as on hands and in food and water.
TENT4 function
In normal human biology, TENT4 is part of an RNA modification process during cell growth. Essentially, HAV hijacks TENT4 and uses it to replicate its own genome.
This work suggested that stopping TENT4 recruitment could stop viral replication and limit disease. Lemon’s lab then tested the compound RG7834, which had already been shown to actively block the hepatitis B virus by targeting TENT4.
Now researchers detail the precise effects of oral RG7834 on HAV in the liver and feces, and how the ability of the virus to cause liver injury is dramatically diminished in mice that have been genetically engineered to develop HAV infection and disease. VHA. Research Suggests Compound Was Safe at the dose used in this investigation and in the acute time frame of the study.
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