Project Summary / Abstract
Cytomegalovirus (CMV) is the most common congenital infection and the leading cause of birth defects in
children in the United States. While the urgent need for a vaccine against congenital CMV is widely recognized,
the underlying mechanisms responsible for the poor generation and inadequate maintenance of immunity remain
undefined, thus compromising our ability to create effective methods for prevention and treatment. The goal of
this proposal is to use a murine model of congenital CMV to identify both the mechanisms and consequences of
failing to control CMV in early life. Since immune control of CMV is largely dependent upon CD8+ T cells, we
have focused our studies on understanding why CD8+ T cells in early life fail to control congenital CMV infection.
Based on our published studies and new preliminary data, we hypothesize that neonatal CD8+ T cells have an
inherent propensity to become functionally exhausted during CMV infection, leading to prolonged viral shedding
and the altered development of the CD8+ T cell compartment. In the first aim, we will determine why neonatal
CD8+ T cells fail to control CMV during the acute stage of infection and attempt to revive immune functionality
by blocking inhibitory receptors. In the second aim, we will examine why CD8+ T cells made after infection fail
to control ongoing viral replication during the latent stage of infection and attempt to limit viral shedding by
increasing numbers of naïve T cells with IL-7 therapy. Knowledge from these studies is expected to pave the
way for the development of vital preventative and therapeutic strategies against congenital CMV disease.