VACCINATION TO CMV · Dissection of T cell cosignaling and development of vaccination strategies to cytomegalovirus

Cytomegalovirus (CMV, a β-herpesvirus) infects the majority of the world’s population, establishing a lifelong infection. This infection is largely asymptomatic in immune competent hosts, but causes severe disease in immunocompromised neonates and adults. In healthy persistently infected individuals huge numbers of CMV-specific T cells accumulate over time (i.e. “memory inflation”), a process recently associated with the immune risk profile and immune senescence in the elderly. CMV encodes numerous immunomodulatory (or immune-evasion) gene products that target pathways involved in T cell priming and activation, including the regulation of cosignaling molecules such as the B7 molecules. We seek to determine how targeting of these B7 cosignaling systems affects CD4 and CD8 T cell mediated control of MCMV during acute, persistent and latent infection from the virus perspective, using mutant viruses that lack immune evasion genes, as well as from the host perspective by using genetically deficient mice, blocking and stimulating reagents, and adoptive transfers. Additionally, we will investigate the role of other cosignaling molecules (i.e. the stimulating TNFR family members CD27 and OX-40 and the inhibitory CTLA-4 and PD-1 molecules) to determine their precise role during MCMV infection. In this way we will gain more insight in the factors involved in maintaining the delicate balanse between virus and host. Ultimately, we would like to use the obtained knowledge about the role of cosignaling in CMV infection to develop vaccination strategies against (lethal) CMV disease.