Products of US22 genes M140 and M141 confer efficient replication of murine cytomegalovirus in macrophages and spleen

Efficient replication of murine cytomegalovirus (MCMV) in macrophages is a prerequisite for optimal growth and spread of the virus in its natural host .;Simultaneous deletion of US22 gene family members M139, M140, and M141 re sults in impaired replication of MCMV in macrophages and mice. In this stud y, we characterized the proteins derived from these three genes and examine d the impact of individual gene deletions on viral pathogenesis. The M139, M140, and M141 gene products were identified as early proteins that localiz e to both the nucleus and cytoplasm in infected cells. Gene M139 encodes tw o proteins, of 72 and 61 kDa, while M140 and M141 each encode a single prot ein of 56 (pM140) and 52 (pM141) kDa, respectively. No role for the R M139 proteins in MCMV replication in macrophages or mice was determined in these studies. In contrast, deletion of either M140 or M141 resulted in impaired MCMV replication in macrophages and spleen tissue. Replication of the M140 deletion mutant was significantly more impaired than that of the virus lac king M141. Further analyses revealed that the absence of the pM140 adversel y affected pM141 levels by rendering the latter protein unstable. Since the replication defect due to deletion of M140 was more profound than could be explained by the reduced half-life of pM141, pM140 must exert an additiona l, independent function in mediating efficient replication of MCMV in macro phages and spleen tissue. These data indicate that the US22 genes M140 and M141 function both cooperatively and independently to regulate MCMV replica tion in a cell type-specific manner and, thus, to influence viral pathogene sis.