Using the nonhuman primate model of HCMV to guide vaccine development

The natural history of human cytomegalovirus (HCMV) is inextricably associated with mucosal surfaces. The vast preponderance of primary infections occur following mucosal exposure to infectious virions, and the high seroprevalence of HCMV throughout the world is due to long-term excretion of HCMV in bodily fluids from multiple mucosal sites. Accumulating evidence presents a model where the earliest virus-host interactions following infection dictate the long-term pattern of infection, alter innate immune responses that skew adaptive responses to enable persistence within an immune host, and are essential for reinfection of a host with prior immunity. HCMV has evolved a complex repertoire of viral functions fine-tuned to manipulate the immune environment both locally at the sites of infection and systemically within an infected host. Collectively, viral immune modulation represents a significant impediment for an HCMV vaccine. As HCMV can disseminate beyond mucosal surfaces to reinfect immune hosts, it may not matter whether prior immunity results from prior infection or immunization. A better understanding of the earliest virus-hosts interactions at mucosal surfaces may identify elements of the viral proteome that are especially susceptible to vaccine-mediated disruption and prevent challenge virus from disseminating to distal sites, particularly the maternal-fetal interface.