The IFN antiviral response involves a myriad of diverse biochemical pathways that disrupt virus replication cycles at many different levels. As a result, viruses have acquired and evolved genes that antagonize host antiviral proteins. IFNs inhibit viral infections in part through the 2’,5’-oligoadenylate(2-5A) synthetase (OAS)/RNase L pathway. OAS proteins are pathogen recognition receptors that exist at different basal levels in different cell types and are IFN inducible. Upon activation by the pathogen-associated molecular pattern viral double-stranded RNA, certain OAS proteins synthesize 2-5A from ATP. 2-5A binds to the antiviral enzyme RNase L causing its dimerization and activation. Data will be presented showing that disparate RNA viruses, including group 2a betacoronaviruses, and group A rotaviruses, produce proteins with 2’,5’-phosphodiesterase (PDE) activities that eliminate 2-5A thereby evading the antiviral activity of the OAS/RNase L pathway. These viral proteins are members of the eukaryotic-viral LigT-like group of 2H phosphoesterases, so named for the presence of 2 conserved catalytic histidine residues. AKAP7, a related mammalian 2H phosphoesterase, also rapidly degrades 2-5A with kinetics similar to that of mouse hepatitis virus (MHV) ns2 and rotavirus VP3 proteins. Furthermore, the AKAP7 PDE domain can complement an inactive MHV ns2 gene in vitro and in vivo in mouse liver. We suggest the possibility that viral acquisition of the host AKAP7 PDE domain might have occurred during evolution, allowing some RNA viruses to antagonize the RNase L pathway and thereby evade antiviral innate immunity.