Unique Mutations in Mouse Hepatitis Virus Reduce Virus Replication: Preclinical Findings

Synopsis

All coronaviruses contain a small domain called the macrodomain, or Mac1, within the nonstructural protein 3 (nsp3). Mac1 binds to and removes a molecule called mono-ADP-ribose (MAR) that attaches to proteins. Although Mac1 is known to be important for viral virulence, its specific roles inside cells are not fully understood. Most research has focused on a single mutation affecting how Mac1 binds MAR. To explore additional functions, researchers studied different Mac1 mutations in a mouse coronavirus (MHV). One mutation had no effect on the virus, while two others significantly weakened viral replication in immune cells and reduced disease severity in animals. One mutation caused greater viral attenuation but still partially suppressed immune responses. Combining both mutations made the virus non-viable, indicating that multiple Mac1 activities are essential for viral replication. These findings demonstrate that Mac1 performs several critical functions supporting coronavirus replication and highlight it as a promising target for antiviral drug development.

Journal

Journal of Virology