Hepatitis C Among Viruses Targeted by Innate Immunity-triggering Compounds

Hepatitis C Among Viruses Targeted by Innate Immunity-triggering Compounds

Researchers at the University of Washington have identified a novel class of immune modulatory molecules that promote innate immune responses to a range RNA viruses, including hepatitis C — a promising discovery that might lead to broad-spectrum antiviral drugs. The research paper, titled “Targeting innate immunity for antiviral therapy through small molecule agonists of the RLR pathway,” was published in the Journal of Virology.

When viral infection occurs, the cellular response is initiated with viral pathogen-associated molecular patterns (PAMPs) being engaged by pathogen recognition receptors (PRR), proteins expressed by the cells of the innate immune system. This event sets in motion a series of processes that culminate in the activation of transcription factor IRF3, a key player in antiviral immunity and one whose activation leads to the expression of several innate immune response genes. Researchers theorized that molecules that activate IRF3 will induce broad-ranging antiviral innate immunity.

The team identified small molecules that activate IRF3, and tested a lead compound and its derivatives for their ability to suppress infection by a number of RNA viruses, especially relevant due to these viruses high mutation rates, high re-emergence rates, and few therapeutic options. The scientists observed that administration of these compounds significantly decreased the viral RNA load in cultured cells that had been infected with the hepatitis C virus, West Nile virus and dengue virus, as well as with viruses of the families Filoviridae (Ebola), Orthomyxoviridae (influenza A), Arenaviridae (Lassa) and Paramyxoviridae (respiratory syncytial virus, Nipah).

“Our compound has an antiviral effect against all these viruses,” said Michael Gale Jr., a professor of immunology and director of the UW Center for Innate Immunity and Immune Disease.

The approach was able to activate innate immunity, a process that targets the infected cell instead of the virus itself, thus making it less likely to develop resistance. Knockdown studies identified the mechanism behind this response to be the PRR RIG-I-like receptor pathway.

The next steps include research into safe dose levels and stability in animals and, eventually, humans. Shawn Iadonato, chief scientific officer at Seattle biotech Kineta, which assisted in the research, said in a press release, “There is tremendous interest in triggering innate immunity. It’s routine for us to think of broad-spectrum antibiotics, but the equivalent for virology doesn’t exist.”

New therapies that might treat diseases caused by viral infection, such as hepatitis C, are in demand. According to the World Health Organization, approximately 500,000 people die each year from hepatitis C-related liver diseases. Although antiviral drugs have a high rate cure, reducing a patient’s risk of liver cancer and cirrhosis, access to diagnosis and treatment is still limited.

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