Scientists Discover the Key to Hepatitis A Virus Replication and Show the Effectiveness of the Drug-ScienceDaily

The results of these surveys are Minutes of the National Academy of SciencesIs the first to show effective drug treatment for HAV in an animal model of this disease.

“Our study is to target this protein complex with orally administered small molecule therapies to stop viral replication in a mouse model of hepatitis A, reverse liver inflammation, and antivirus. Proving the principle of therapy and hepatitis A in the situation in which it occurred. “

Lemon, a member of the Walter Reed Army Medical Center’s research team who developed the first inactivated HAV vaccine to be administered to humans in the 1970s and 1980s, was introduced after the vaccine became widely available in the mid-1990s. He said HAV studies were declining. Cases plummeted in the 2000s as vaccination rates soared. Researchers have turned their attention to the hepatitis B and C viruses, which are very different from HAV and cause chronic diseases. “It’s like comparing an apple to a turnip,” Lemon said. “The only similarity is that they all cause liver inflammation.” HAV is not part of the same viral family as hepatitis B and C viruses.

HAV vaccines are very effective, but the incidence of hepatitis A has increased since 2016. Lemons are not vaccinated by everyone, and HAV can be present in our hands, food, water and other environments for extended periods of time, resulting in more than 44,000 cases and 27,000 cases in the United States. There have been hospitalizations and 400 deaths. States since 2016, according to the CDC.

There have been several outbreaks in the last few years. In San Diego in 2017, about 600 people became seriously ill and 20 died, mainly due to homelessness and the use of illegal drugs. In 2022, there were small outbreaks associated with multiple organic strawberries. The state leads to about 12 hospitalizations. Another outbreak in 2019 was related to fresh blackberries. Worldwide, tens of millions of HAV infections occur each year. Symptoms include fever, abdominal pain, jaundice, nausea, loss of appetite, and loss of taste. Once you get sick, there is no cure.

In 2013, Lemon et al. Discovered a dramatic change in the hepatitis A virus in the human liver. When the virus leaves the liver cells, it hijacks part of the cell membrane and hides from the antibodies that would have isolated the virus before it spread throughout the bloodstream.This work was published in Nature It provided insights into how much researchers haven’t learned about the virus, which was discovered 50 years ago and is likely to have caused a disease dating back to ancient times.

A few years ago, researchers discovered that the hepatitis B virus requires TENT4A / B for its replication. Meanwhile, Lemon’s lab led an experiment searching for the human protein required for HAV to replicate, and discovered ZCCHC14, a specific protein that interacts with zinc and binds to RNA.

“This was a turning point in this current study,” Lemon said. “ZCCHC14 was found to bind very specifically to specific parts of the RNA of HAV, a molecule that contains the genetic information of the virus. As a result of that binding, the virus can mobilize TENT4 from human cells. I can do it.”

In normal human biology, TENT4 is part of the RNA modification process during cell proliferation. Basically, HAV hijacks TENT4 and uses it to replicate its own genome.

This study suggested that stopping the recruitment of TENT4 could stop viral replication and limit the disease. Next, Lemon’s lab tested compound RG7834, which was previously shown to actively block hepatitis B virus by targeting TENT4.In PNAS In the paper, researchers found that the exact effect of oral RG7834 on liver and fecal HAV and the ability of the virus to cause liver damage in mice genetically modified to develop HAV infection and disease are dramatically reduced. I explained the method in detail. Studies suggest that the compound was safe at the dose used in this study and in the acute time frame of the study.

“This compound is far from human use, but it shows the way to an effective way to treat illnesses that we haven’t received at all,” Lemon said.

Pharmaceutical company Hoffmann-La Roche has developed the RG7834 for use in chronic hepatitis B infections and tested it in humans in Phase 1 trials, but in animal studies it is too toxic to be used for long periods of time. It was suggested that there was sex.

“Treatment for hepatitis A is short-term, and more importantly, our group and others are working on compounds that reach the same target without the effects of toxicity,” Lemon said. Said.

This study was a collaborative effort between the Lemon Lab and Jason Whitmere’s Lab, a professor of genetics at UNC School of Medicine. Lemon and Whitmire are members of the UNC Lineberger Comprehensive Cancer Center.

The lead authors of the PNAS paper are YouLi and Ichiro Misumi. All other authors belong to UNC, Tomoyuki Shioda, Lu Sun, Erik Lenarcic, Hyejeong Kim, Takayoshi Shirasaki, Adriana Hertel-Wulff, Taylor Tibbs, Joseph Mitchell, Kevin McKnight, Craig Cameron, Nathaniel Moorman, David McGivern. , John Cullen, Jason. K. Whitmere and Stanley M. Lemon.

This work is funded by the National Institute of Infectious Diseases (R01-AI131685), (R01-AI103083), (R01-AI150095), (R21-AI163606), (R01-AI143894), (R01-AI138337). It was supported. The UNC Pathology Service Core and UNC High Throughput Sequence Facility were partially supported by the National Cancer Center Center Core Support Grant (P30CA016086) to the UNC Rheinberger Comprehensive Cancer Center.