Viruses can only spread inside of a host and cause disease if their replication cycle is successful. The UNC School of Medicine researchers studied that cycle in the hepatitis A virus (HAV) and found that replication needs particular interactions between the human protein ZCCHC14 and a family of enzymes termed TENT4 poly(A) polymerases.
Additionally, they discovered that the oral drug RG7834 halted viral replication at a critical stage, preventing liver cell infection.
These findings are the first to show that pharmacological treatment for HAV is effective in an animal model of the illness and were published in the Proceedings of the National Academy of Sciences.
This new research shows “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,” points out senior author Stanley M. Lemon.
The first inactivated HAV vaccine to be given to humans was produced by a research team at the Walter Reed Army Medical Center in the 1970s and 1980s, according to Lemon. After the vaccine became widely available in the mid-1990s, research on HAV slowed down.
As vaccination rates soared in the 2000s, the number of cases fell. The hepatitis B and C viruses, which differ greatly from HAV and also cause chronic disease, caught the interest of researchers.
“It’s like comparing apples to turnips,” Lemon remarks. “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.
Since 2016, there have been more outbreaks of hepatitis A, even though the HAV vaccine is very effective. Since 2016, the CDC reports that there have been more than 44,000 cases, 27,000 hospitalizations, and 400 deaths in the United States as a result of HAV. According to Lemon, not everyone is vaccinated, and HAV can exist for long periods of time in the environment, such as on our hands and in food and water.
Over the past few years, there have been a number of outbreaks, including one that killed 20 people and sickened 600 people in San Diego in 2017. This outbreak was mostly caused by homelessness and drug use. A minor outbreak associated with organic strawberries occurred in several states in 2022 and resulted in roughly a dozen hospitalizations.
In 2019, fresh blackberries were linked to another outbreak. Tens of millions of HAV infections take place annually throughout the world. Fever, stomach ache, jaundice, nausea, as well as loss of taste and appetite, are some of the symptoms. There is no cure once you are sick.
Lemon and colleagues discovered in 2013 that the hepatitis A virus undergoes significant modifications within the human liver. As it exits liver cells, the virus snares pieces of the cell membrane to disguise itself from antibodies that may have otherwise contained it before it spread far in the bloodstream.
This research, which was published in Nature, revealed how much is still unknown about the virus that was first identified 50 years ago and is thought to have been the source of disease as far back as ancient times.
A few years ago, scientists discovered that the hepatitis B virus needed TENT4A/B to replicate. In the meantime, tests conducted in Lemon’s lab identified ZCCHC14, a specific protein that interacts with zinc and binds to RNA, as being required by humans for HAV to reproduce.
Lemon remarked that this was the turning point in the current investigation.
“We found ZCCHC14 binds very specifically to a certain part of HAV’s RNA, the molecule that contains the virus’s genetic information. And as a result of that binding, the virus is able to recruit TENT4 from the human cell.”
In a normal human body, TENT4 is part of a process that changes RNA as cells grow. TENT4 is essentially taken over by HAV, which then uses it to reproduce its own genome.
According to this research, preventing TENT4 recruitment could halt viral replication and reduce illness. The substance RG7834, which had previously been demonstrated to actively stop the Hepatitis B virus by targeting TENT4, was then put to the test in Lemon’s lab.
In the study, the researchers provided specific information on how oral RG7834 affects HAV in the liver and faeces as well as how the virus’s capacity to produce liver damage is significantly reduced in mice that have been genetically modified to acquire HAV infection and disease. The research shows that the compound was safe at the dose used in the study and for the short amount of time it was studied.
“This compound is a long way from human use,” according to Lemon, “But it points the path to an effective way to treat a disease for which we have no treatment at all.”
In a phase 1 trial, Hoffmann-La Roche, a pharmaceutical company, tested RG7834 on people to see if it may treat chronic hepatitis B infections. However, animal tests indicated that it might be too hazardous for long-term usage.
“The treatment for Hepatitis A would be short-term,” Lemon adds, “and, more importantly, our group and others are working on compounds that would hit the same target without toxic effects.”
Image Credit: Maryna Kapustina, UNC School of Medicine
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