Hepatitis D virus is a so-called satellite virus. Its genetic blueprint contains only a single protein, and it uses components of the hepatitis B virus (HBV) as a shell. It therefore depends on the presence of HBV, and the hepatitis B vaccination also protects against HDV. Nevertheless, HDV is responsible for the most severe form of viral hepatitis. In addition to the previous therapy with interferon-alpha, Hepcludex has recently become available as a drug that can effectively prevent HDV from entering liver cells. However, Hepcludex has no direct antiviral effect and cannot prevent the daughter cells from also carrying the virus when infected liver cells divide. Researchers are therefore looking for new antiviral agents for combination therapy.
Dr Arnaud Carpentier, a postdoctoral researcher at the Institute of Experimental Virology at TWINCORE, is an expert in stem cell-based infection models and has now developed one for the study of HDV infections. “Our stem cell-based cell culture system is a valuable model to study viral infections,” says Carpentier. “The cells are almost identical to primary liver cells and therefore offer more realistic conditions than the liver cell lines previously used in hepatitis research.”
To gain a more precise insight into the processes that occur during HDV infection, Carpentier and his team have examined gene activity in the infected cells in more detail. To do this, they used a technique known as single-cell sequencing. “On the basis of the sequencing, we can divide the HDV infected cells into two groups,” says Carpentier. “In some of the infected cells, the virus replicates actively, while in the other half it is unable to reproduce.” The sequencing results showed a crucial difference between the two cell populations: the expression of the gene IRF1.
IRF1 stands for Interferon Regulatory Factor 1. “IRF1 is a transcription factor that plays a role in cellular immune defence,” says Frauke Lange, a doctoral student in Carpentier’s team, and first author of the article. “In this work, we show that IRF1 overexpression inhibits HDV infection. IRF1 also prevents the spread of the virus during cell division, a step not targeted by Hepcludex.”
IRF1 regulates 101 downstream genes. Lange now hopes to identify the downstream genes that exert the observed antiviral effect against HDV. “That's why we want to take a closer look at the genes regulated by IRF1 in the future”, she says. The current results pave the way for the development of new treatment of HDV infection to be used in association with Hepcludex.
