The HCMV chemokine receptor UL78 is required for efficient viral reactivation from latent infection in CD34+ HPCs 4278

Abstract Description Human cytomegalovirus (HCMV) is a ubiquitous pathogen that persists throughout the host’s lifetime. Despite a robust immune response against HCMV, viral clearance cannot be achieved due to the establishment of viral latency within CD34+ hematopoietic progenitor cells (HPCs) and CD14+ monocyte reservoirs. HCMV encodes four putative G protein-coupled receptors (GPCRs) with homology to cellular chemokine receptors. While the roles of three HCMV vGPCRs have been well explored, a definitive role for UL78 in viral latency and reactivation has yet to be elucidated. Utilizing in vitro CD34+ HPC models, we demonstrate that a recombinant virus lacking UL78 protein expression fails to efficiently reactivate from latent infection despite maintaining viral genomes. The observed deficit in viral reactivation was not due to aberrations in lytic replication as this virus exhibited normal replication kinetics in primary fibroblasts. We show that UL78 predominantly couples to the Gαi family of G proteins via a conserved DRL motif located within the second intracellular loop. In a similar manner, we show that recombinant viruses with mutations in the DRL motif of UL78 fail to reactivate from latent infection. To determine proximal proteins and candidate interactors of UL78, we conducted proximity-dependent labeling experiments in infected fibroblasts. Together, our results provide novel insights into the function of UL78, previously unknown to contribute to reactivation from latent infection. Funding Sources This work was supported by NIH P01AI127335 and T32AI170496-01A1 Topic Categories Cytokines and Chemokines and Their Receptors (CCR)