All gammaherpesviruses studied to date block host gene expression through widespread mRNA degradation, yet the contribution of this function towards the viral lifecycle remained unknown. Here we analyzed the impact of host shutoff both in tissue culture and in vivo infections with the murine gammaherpesvirus MHV68, and we found this activity to be largely dispensable for acute lytic replication yet critical for the downstream viral accumulation in the lymph nodes and subsequent establishment of latency in the spleen. These results were unexpected given that MHV68-induced host shutoff is executed by muSOX, a viral protein whose expression has only been detected during the lytic cycle [38, 39, 40] . In addition, the role for muSOX-induced mRNA turnover clearly diverges from that of the alphaherpesvirus host shutoff factor vhs, which similarly induces global mRNA degradation but plays a critical role during acute replication in vivo [41, 42, 43] . The severe attenuation of HSV-1 and HSV-2 vhs mutants is hypothesized to be a consequence of ineffective immune evasion, as vhs blocks dendritic cell activation and down-regulates the type I interferon response [44, 45, 46] . In contrast, we find little difference between MHV68.MR and MHV68.DHS during acute replication in mice, suggesting that while alpha-and gammaherpesviruses block host gene expression via analogous mechanisms, the functional ramifications of this activity are distinct, and may relate to the unique in vivo biology of each class of virus.