Modeling the muSOX three-dimensional structure from the KSHV SOX or EBV BGLF5 crystal structure [21, 47] indicates that amino acid R443 is positioned on the outer surface, away from the catalytic core where nucleic acids are presumably cleaved (data not shown). Although SOX, BGLF5, and muSOX are functionally homologous and likely induce mRNA degradation through a similar mechanism, the identified amino acid mutations that selectively remove host shutoff activity are not conserved, nor are they positioned in the same three-dimensional region. Likely these different mutations alter the local structure of each protein thereby inhibiting or weakening the mRNA or co-factor interactions which contribute to overall mRNA degradation. In this regard, we anticipate that the residual host shutoff activity observed upon infection with the MHV68.DHS virus is at least partially due to incomplete inactivation of muSOX mRNA turnover activity by the R443I mutation.