Alphaviruses are arthropod-borne viruses with RNA genome that are transmitted by mosquitoes and attack the brain. Once the host cells are infected, the viral RNA induces the antiviral pathway - the interferon inducible oligoadenylate synthetase (OAS) / endoribonuclease L (RNAse L) system. The OAS/RNAse L system induces apoptosis and blocks the viral infection. Studies on Ebola, HCV, Influenza, Vaccinia and HIV showed that specific viral proteins can inhibit this system but the process is yet to be elucidated. The EU-funded ALPHA (Alphavirus-specific mechanisms of OAS/RNAse L pathway inhibition, study of non-structural proteins and search for inhibitors) project aimed to understand the molecular mechanisms through which alphaviruses evade host immune response. The ALPHA team successfully solved the crystal structure of a viral protein ChikV in complex with a 2-5A trimer. Functional characterisation of the binding domain using microscale thermophoresis followed. This complex formation was found to be essential for subsequent viral escape. Scientists expressed and purified the inhibitory viral protein nsP1 from Venezuelan equine encephalomyelitis virus and characterised it enzymatically and biophysically. This protein was used as a new antiviral target to find new compounds for virus inhibition. The results of ALPHA explored previously insufficiently characterised alphaviruses and shed the light on the molecular mechanisms of evasion from cellular antiviral responses.
Alphaviruses, evade, OAS/RNAse L, viral protein nsP1, Venezuelan equine encephalomyelitis, inhibition