Gene products of the embedded m41/m41.1 locus of murine cytomegalovirus differentially influence replication and pathogenesis

Cytomegaloviruses utilize overlapping and embedded reading frames as a way to efficiently package and express all genes necessary to carry out a complex lifecycle. Murine cytomegalovirus encodes a mitochondrial-localized inhibitor of Bak oligomerization (vIBO) from m41.1, a reading frame that is embedded within the m41 gene. The m41.1-encoded mitochondrial protein and m41-encoded Golgi-localized protein have both been implicated in cell death suppression; however, their contribution to viral infection within the host has not been investigated. Here, we report that mitochondrial-localized m41.1 (vIBO) is required for optimal viral replication in macrophages and has a modest impact on dissemination in infected mice. In contrast, Golgi-localized m41 protein is dispensable during acute infection and dissemination as well as for latency. All together, these data indicate that the primary evolutionary focus of this locus is to maintain mitochondrial function through inhibition of Bak-mediated death pathways in support of viral pathogenesis.

► MCMV m41/m41.1 cell-death suppressor locus promotes infection in the host.
► Golgi-localized m41 is dispensable for MCMV infection of the host.
► Mitochondrial m41.1 (vIBO) blocks Bak-mediated apoptosis to support dissemination.
► m41.1 (vIBO) subverts death to promote MCMV replication in macrophages.