Roseoloviruses and their modulation of host defenses

•The host antiviral response is sophisticated and the host is well-equipped to eradicate viruses.•The β-herpesviruses have evolved mechanisms to undermine host antiviral responses.•More roseolovirus host evasion mechanisms are likely still to be discovered. Human cytomegalovirus (HCMV), the prototypical human β-herpesvirus, encodes approximately 40 known gene products that function to subvert our host defense mechanisms. From HCMV, we have learned about interferon signaling, cytokine function, chemokine signaling, natural killer (NK) cells’ cytotoxicity toward tumors and virus-infected cells, antigen processing and presentation, and protective initiation of the apoptotic signaling cascade. With each successive discovery of novel host evasion mechanism encoded by the cytomegaloviruses, we illuminate what these herpesviruses have learned over the course of their 100 MYr-long evolution with their hosts. As much as we have learned from HCMV, the other members of the human β-herpesvirus family, HHV-6 and HHV-7, are closely-related and yet largely unexplored. These viruses likely have much yet to teach us.