Boosting IRF1 protein prevents growth of hepatitis D virus in study
Researchers develop stem cell-based infection model to study viral infections
Increasing the levels of a protein called IRF1 helps suppress infection of the hepatitis D virus (HDV) and its growth inside of cells, a new study reports.
“In this work, we show that IRF1 [overproduction] inhibits [or suppresses] HDV infection … [and] prevents the spread of the virus during cell division, a step not targeted by Hepcludex,” Frauke Lange, the study’s first author and a doctoral student at the Institute of Experimental Virology at TWINCORE, in Germany, said in an institute press release.
Hepcludex is the brand name of bulevirtide in Europe, where it’s approved to treat certain chronic hepatitis D patients, but is not cleared for use in the U.S. The therapy is designed to stop HDV from getting into liver cells, but it cannot stop the virus from growing once it’s already infected cells.
IRF1 may be new potential antiviral treatment for hepatitis D
The study’s findings point to IRF1 as a new potential antiviral treatment for hepatitis D that can be used together with other available antiviral therapies like Hepcludex, the researchers noted.
The study, “Single cell analysis of mature hepatocytes reveals an IRF1 driven restriction of HDV infection,” was published in JHEP Reports.
Hepatitis refers to liver inflammation, which usually occurs as a result of a viral infection, the most common being hepatitis B.
The hepatitis D virus, which causes hepatitis D, is able to infect only people who are already infected with the hepatitis B virus (HBV). When both viruses are present, the infection tends to be very severe and can lead to serious liver injury.
In the new study, researchers set out to examine how HDV grows in the liver using hepatocyte-like cells, a cellular model of adult hepatocytes, or liver cells. Essentially, this model involves using stem cells, which can give rise to nearly all types of cells, to grow hepatocyte-like cells in a lab dish.
The lab-grown liver-like cells can then be used to examine how the virus infects cells and grows, or multiplies, inside them.
“Our stem cell-based cell culture system is a valuable model to study viral infections,” said Arnaud Carpentier, PhD, the study’s senior author and a postdoctoral researcher at the Institute for Experimental Virology. “The cells are almost identical to primary liver cells [those directly isolated from liver tissue] and therefore offer more realistic conditions than the liver cell lines previously used in hepatitis research.”
The researchers infected the hepatocyte-like cells with HDV, then conducted detailed genetic analyses to examine the growth of the virus in individual cells. They found that the virus was growing well in some of the cells, but not in others.
“We can divide the HDV infected cells into two groups,” Carpentier said. “In some of the infected cells, the virus replicates [multiplies] actively, while in the other half it is unable to reproduce.”
Researchers find link between IRF1 protein, HDV
Further investigation revealed that the cells where HDV couldn’t grow efficiently were producing higher levels of the IRF1 protein. IRF1, which stands for interferon regulatory factor 1, regulates the activity of several genes and helps to coordinate the immune system’s response against viral infections.
The researchers found that, if they decreased IRF1 levels by half in hepatocyte-like cells, the HDV was able to grow more efficiently, by about 10 times.
Consistently, increasing IRF1 levels in lab-grown liver cancer cells — which are susceptible to HDV infection — restored the activity level of genes regulated by IRF1 and suppressed HDV infection by about half after seven days.
IRF1 was found to restrict HDV infection at a cytoplasmic stage of the viral cycle. The cytoplasm is the semifluid solution that fills the space between the nucleus (where all genetic information is stored) and the cell membrane.
The IRF1 protein works to help control the activity of more than 100 different genes that are involved in immune responses. “That’s why we want to take a closer look at the genes regulated by IRF1 in the future,” Lange said.
The researchers hope to investigate which of these genes are involved in IRF1’s anti-HDV activity.
They also think that therapies to boost IRF1 levels or increase the activity of genes it controls could prevent the growth of HDV within cells and stop the virus from spreading when cells divide, meaning such therapies could theoretically act in synergy with Hepcludex.
“Our work narrows down the search for new potent cellular antiviral effectors,” the researchers wrote, adding that further understanding of such antiviral mechanisms “may provide valuable insights into the development of new antiviral strategies that could be applied in combination with Hepcludex.”
About the Author
