Interferon-Stimulated Gene Inhibits HCV Replication

A new study sheds light on how the immune system reacts to hepatitis C viruses (HCV) and how a novel antiviral mechanism is expressed.

The study, published in the Journal of Hepatology, shows how the interferon (IFN)-stimulated gene C19orf66 disrupts the formation of HCV viral replication machinery.

"In order to find out whether the C19orf66 gene is increasingly activated in samples from hepatitis C patients, we first examined liver tissue samples from infected and healthy people," Volker Kinast, a PhD student at Ruhr-Universität Bochum said in a news release.

"In the next step, we checked whether C19orf66 has an antiviral effect against hepatitis C viruses,” Kinast continued. “We conducted experiments using cells that contained a lot of C19orf66 and cells that contained only a little of it. We then observed that the hepatitis C virus replicates much more slowly in cells that contain a lot of C19orf66 than in control cells."

The study included virological, biochemical, and genetic approaches as well as correlative light, electron microscopy, transcriptome, and proteome analysis.

By remodeling endoplasmic reticulum-derived membranes to create an accumulation of vesicles, HCV induces the formation of a membranous web (MW), where viral RNA replication is thought to occur. The study demonstrated that expression of C19orf66 altered MW formation, interfering with virus replication.

The investigators also found that peg IFN-α/ribavirin therapy induced C19orf66 expression in patients with chronic hepatitis C. Investigators further determined that the zinc-finger motif is crucial for C19orf66’s restriction capacity and ability to accumulate.

“C19orf66 is an IFN-stimulated gene, which is upregulated in hepatocytes within the first hours post IFN-treatment or HCV infection in vivo,” the study authors concluded. “The encoded protein possesses specific antiviral activity against HCV and targets the formation of the membranous web. Our study identifies C19orf66 as an IFN-inducible restriction factor with a novel antiviral mechanism specifically targeting HCV replication.

The study was funded by Helmholtz-Alberta-Initiative - Infectious Disease Research, the Swiss National Science Foundation, and the German Research Foundation. It was led by Eike Steinmann, MD, PHD, at the Department for Molecular and Medical Virology at Ruhr-Universität Bochum in Germany.

About 71 million people are living with hepatitis C virus. Antiviral treatments cure most HCV infections, but only about 20% of people with the virus are aware of their infection, which can lead to chronic illness that damages the liver and often requires liver transplantation.

Health leaders have an eye toward eliminating hepatitis C infections by 2030, according to the World Health Organization, which has endorsed the goal in the Global Health Sector Strategy. Advancements in diagnosis and treatment are key to meeting this lofty goal.

The US Centers for Disease Control and Prevention has called for increased screenings for HCV, including HCV screening at least once for all adults aged 18 years or older and for women during each pregnancy. Advancements in the treatment of the disease have included novel oral therapies for treating HCV in adolescents.