Host shutoff has been hypothesized to play a role in the diversion of gene expression resources and machinery towards the virus during lytic replication [16, 48] , as well as general immune evasion through the down-regulation of immune stimulatory factors [49] . Our failure to detect a significant replication defect for MHV68.DHS during a multi-step growth curve in cultured murine fibroblasts or in the mouse lung implies that resource reallocation is unlikely to be the primary role for muSOX-induced mRNA depletion. Likewise, the similar viral titers in the lungs of mice infected with MHV68.MR or MHV68.DHS argues against a role for muSOX in the general suppression of host innate immune responses Because MHV68.DHS still retains residual mRNA degradation activity, it is possible that some degree of host shutoff could be important for viral replication. However, the appearance of significant defects in downstream viral events even with a partial host shutoff defect further strengthens our conclusion that host shutoff plays a vital role in the lifecycle and pathogenesis of MHV68 in vivo.