Human cytomegalovirusinduces neuronal geneexpression to promote virionmaturationin macroH2A1-dependent manner​

Human cytomegalovirus (HCMV) uniquely remodels host cells, generating a cytoplasmic viral-induced assembly compartment (vIAC) and a kidney-bean-shaped nucleus. How these stark morphology changes take place in the context of host gene regulation is still emerging. Here, we discovered that HCMV titers, but not virus particle numbers, were significantly reduced in the absence of the histone variant macroH2A1, indicating that macroH2A1 is essential for producing infectious progeny. Because virion maturation and cellular remodeling are closely linked processes, we used confocal and electron microscopy to define structural changes in the host cell. We uncovered that HCMV-induced reorganization of the host nucleus, cytoskeleton, and endoplasmic reticulum does not occur in the absence of macroH2A1. Furthermore, we discovered using RNA-seq that while all viral genes were highly expressed in the absence of macroH2A1, many HCMV-induced host genes were not. Hundreds of these HCMV-induced macroH2A1-dependent host genes are associated with neuronal synapse formation and vesicle trafficking. Knock-down during infection of several HCMV-induced neuronal genes resulted in malformed vIACs and smaller plaques, establishing their importance to HCMV infection. Together, our findings demonstrate that HCMV manipulates host gene expression to hijack the dormant neuronal secretory pathway for proper virion maturation. RNA-seq of WT and macroH2A1 KO HFF-t cells from 3 separate infections with Towne CMV at an MOI of 1 and harvested at 4,16,24,48,72 hours post infection. Uninfected aka "mock" cells included as control.