PROJECT SUMMARY/ABSTRACT – O’CONNOR, CHRISTINE M.
Human cytomegalovirus (HCMV) is a wide-spread pathogen, infecting the majority of the
population in the United States. This virus poses a significant threat to developing
fetuses as well as to children and adults who lack a competent immune system, often
causing severe disease and mortality. Once individuals acquire an HCMV infection, the
virus remains with the host for life, in a latent or quiescent state in the hematopoietic
compartment. During times of severe immunological stress, the virus reactivates to its
active state, allowing for dissemination and subsequent disease. With the exception of
the immuno-naïve and sero-negative organ transplant recipients, primary infection with
HCMV rarely causes disease, but rather it is reactivation that leads to significant
complications. Thus, to prevent HCMV-associated disease, we must gain a complete
understanding of viral latency and reactivation. One of a handful of genes encoded
during latency is one of the four viral G protein-coupled receptors (GPCRs), US28. We
have shown previously that US28 is required for the establishment and maintenance
latency and that US28-mediated signaling contributes to these effects. We have also
found that US28 modulates the expression of specific cellular targets that regulate the
Major Immediate Early Promoter (MIEP), a master regulator in the latent-to-lytic switch.
Therefore, we hypothesize that US28 modulates specific host signaling pathways to
regulate transcriptional silencing of the MIEP to facilitate HCMV latency. To explore this
hypothesis, we will take advantage novel approaches coupled with our arsenal of US28-
specific recombinants, as well as both in vitro and ex vivo latency model systems. In Aim
1, we will define mechanisms underlying US28-mediated attenuation of AP-1
transcription factor binding to the MIEP during latency by examining the upstream
signaling pathways that regulate AP-1. In Aim 2, we will determine the factors that recruit
YY1 to the MIEP during latency by assessing US28-regulated signaling pathways and
factors that promote the binding of this repressive transcription factor. In sum, the
experiments proposed herein will lead to a greater understanding of US28’s biological
functions during latency and will lay the foundation for future studies to develop novel
therapeutics specifically targeting the latent reservoir of HCMV infection.