Human cytomegalovirus (HCMV) is a pervasive herpesvirus that resides latently in early myeloid lineage cells of ~70% of the population. Latent infection is typically asymptomatic in healthy individuals, however reactivation under immune compromised conditions leads to lytic infection, which can be life threatening. HCMV is implicated in cardiovascular disease (CVD) progression, and infection with HCMV increases risk of future development of CVD by 22%. HCMV promotes progression of atherosclerosis at all stages, from initial injury at the endothelium through plaque formation. However, mechanisms underlying HCMV latency, reactivation, and increased risk for CVD remain unclear. A contributing factor implicated in these processes is US28, an HCMV-encoded G protein-coupled receptor. This viral signaling protein is expressed during latency, and my lab has shown US28 is necessary for latent infection. We also showed US28 signaling is required for establishment and maintenance of latent infection, however our understanding of US28 regulation of latency and its role in progression of the cellular processes involved in atherosclerosis remains incomplete. To better understand US28s impact on latency, I identified cellular genes US28 dysregulates using microarray. I found US28 expression during latency increases cellular MNDA, which activates transcriptional repressor Yin Yang 1 (YY1). I found US28 also increases the binding of YY1 to the major immediate early promoter (MIEP), a key regulator of HCMVs latent-to-lytic switch. Further, I found US28 increases binding of latently-infected cells to an activated endothelial monolayer through membrane-bound fractalkine (FKN). These data suggest a role for US28 in aiding in latency and cellular processes involved in atherosclerosis. The goals of this proposal are to determine if US28-mediated regulation of MNDA and YY1 is sufficient to confer the latent phenotype in myeloid cells and define the impact of US28s interaction with FKN in increasing cellular adhesion and transmigration, processes pertinent to the progression of atherosclerotic plaque formation. Successful completion of this proposal will provide insight into how US28 silences the MIEP to promote HCMV latency and bolster our understanding of HCMV-induced progression of atherosclerosis. These studies may inform future development of novel therapeutics to target US28, the HCMV latent reservoir, and the progression of HCMV-related diseases such as atherosclerosis.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|