Human cytomegalovirus (HCMV), a member of the herpesvirus family, typically produces few if any symptoms in otherwise healthy individuals, but often causes life-threatening infections in newborns, solid organ and hematopoietic stem cell transplant recipients, and other immunocompromised patients. In addition to its medical importance, HCMV is also a useful model system for the study of translational regulation of eukaryotic gene expression and evolution of large DNA viruses.
Host cells respond to viral infections by activating several antiviral pathways, including ones that are triggered by interferons and activated by double-stranded RNA (dsRNA), and that act by shutting off protein synthesis. To enable the continued protein synthesis that is necessary for replication, many viruses including HCMV have evolved means of inactivating these pathways. A genetic screen identified two HCMV genes that participate in maintaining translational capacity in the infected cell despite activation of these host responses. These genes bind to dsRNA through an unconventional dsRNA binding domain and a PKR binding domain, both of which are necessary for blocking the antiviral pathways. The proteins also self-associate and cause PKR relocalization to the nucleus, an unprecendented effect among viral anti-PKR protein. A related virus, Mouse CMV, has genes of similar function and comparisons between the human and mouse viruses will be useful in identifying conserved critical functions.
Current efforts aim to elucidate the activities of the various domains of these genes and to identify other viral and cellular factors needed to maintain the robust protein synthetic capacity in CMV-infected cells.