Viral and cellular contributions to the epigenetic silencing of viral lytic gene expression during human cytomegalovirus latency

Human cytomegalovirus (HCMV) is a ubiquitous human pathogen that causes birth defects and significant morbidity and mortality in the immunocompromised. HCMV achieves lifelong persistence in its host through the establishment of latency. There is no effective vaccine to prevent HCMV infection, and current antivirals do not affect latent reservoirs. Consequently, complete clearance of HCMV is not currently achievable. A better understanding of the molecular mechanisms underlying viral latency is thus essential for improving treatments for HCMV infection.;The regulation of viral immediate-early (IE) gene expression is a critical control point in determining the outcome of HCMV infection. Viral IE genes are expressed at the beginning of lytic infection but must be silenced during the establishment of latency. Regulation of IE gene expression occurs largely through epigenetic mechanisms. However, how viral genomes are assembled into chromatin and repressed during latency is not well understood. We show here that both canonical and variant histones are deposited onto incoming viral genomes and that the cellular intrinsic defense protein Daxx promotes chromatin assembly on the viral genome. Our findings suggest that initial chromatin assembly on viral genomes is mediated by cellular factors and correlates with transcriptional silencing.;We also addressed how viral factors contribute to the silencing of IE gene expression during latency. We found that the viral UL138 protein represses IE transcription during the establishment of latency by preventing recruitment of cellular lysine demethylases that otherwise activate IE gene expression. Thus our work provides the first evidence for how a viral protein promotes the establishment of latency. We further demonstrate that at least one other viral factor also silences IE gene expression during latency, highlighting the importance of viral control over this process. Overall, we show that the epigenetic silencing of IE gene expression during the establishment of latency is a dynamic process that involves the contributions of both cellular and viral factors.