Molecular Insights into Crimean-Congo Hemorrhagic Fever Virus

Zivcec, Marko; Scholte, Florine E. M.; Spiropoulou, Christina F.; Spengler, Jessica R.; Bergeron, Éric

The L protein regions involved in mRNA transcription and replication of the viral genome likely start with the internal endonuclease domain and include several conserved RdRp motifs [85, 86] . The viral endonuclease cleaves host mRNAs and uses the resulting 5 1 capped oligonucleotides as primers to initiate viral transcription. The 5 1 termini of CCHFV vRNA are monophosphorylated [87, 88] , in contrast to many other RNA viruses that use the more common triphosphate group (5 1 -pppRNA). Monophosphorylated 5 1 genome ends are likely created by a chain initiation mechanism called prime and realign, in which the viral endonuclease generates a 5 1 -pRNA by cleaving off the first nucleotide of the 5 1 genomic end. This mechanism was previously suggested for the related Hantaan virus [89] . Processing of CCHFV genome 5 1 termini to a monophosphate group (5 1 -p) is a possible strategy for evading the innate immune response by blunting the activation of retinoic acid-inducible gene I (RIG-I), which is preferentially activated by 5 1 -pppRNA [87, 88] . Nevertheless, the type-I IFN response to CCHFV requires RIG-I [88] . RIG-I is believed to function not only as a sensor during viral infection, but also as an antiviral effector [90] . This effector function may partially explain why RNA viruses that induce poor IFN responses or do not have the preferred 5 1 -pp or 5 1 -pppRNA RIG-I ligands replicate more efficiently when RIG-I is knocked down [88, 91] .