The M4 gene of murine gammaherpesvirus 68 modulates latent infection

Murine gammaherpesvirus 68 (MHV-68) encodes a set of unique genes, M1, M2, M3 and M4, and eight non-translated tRNA-like molecules that are thought to be important in virus-host interactions and latent infection. The M4 gene is predicted to encode a novel secreted protein. To investigate the role of M4 in viral pathogenesis, a mutant MHV-68 that did not express M4 was constructed and its replication was characterized in vitro and in vivo. Virus replication was identical to the wild type in vitro and no difference could be detected in virus replication in the lung following intranasal infection. However, in the spleen, virus deficient in M4 expression was severely attenuated in the establishment of latency. These results indicate a critical role for M4 in MHV-68 pathogenesis.