The second major defect observed upon MHV68.DHS infection is a marked reduction in the number of infected splenocytes present during peak latency establishment relative to mice infected with wild-type or mutant rescue viruses. This defect could arise simply as a downstream consequence of the aforementioned impairment in trafficking. However, significantly reduced levels of viral DNA are detected in the spleen even after an intraperitoneal infection, which bypasses the need for acute replication in the lung and subsequent trafficking through the lymph nodes [37] . Thus, MHV68.DHS appears defective in both trafficking and latency establishment in the spleen. Such a phenotype might occur if MHV68.DHS-infected cells preferentially entered the lytic cycle, perhaps enabling more efficient clearance by the immune system. This model is supported by our observation that an increased percentage of cultured 3T3 cells infected with MHV68.DHS express lytic markers relative to those infected with MHV68.WT. However, if this represents enhanced entry into the lytic cycle, there must be a downstream defect that tempers subsequent viral output, as the host shutoff mutant virus does not replicate to higher titers in 3T3 cells than the wild-type virus. In this regard, host shutoff could be important for optimizing the balance of host or viral proteins in an infected cell, as has been reported in an EBV mutant lacking BGLF5, where altered levels of proteins inhibited viral maturation and egress [64] . One mechanism that could shift the balance of infection away from latency is if muSOX down-regulates factors that inhibit latency establishment; such negative regulators would then accumulate in the presence of the R443I mutant, driving cells into lytic replication. MuSOX activity may also be required for the virus to achieve the appropriate level of host and or viral factors packaged into the viral particle in order to efficiently establish latency in newly infected cells rather than enter the lytic cycle.