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Transcriptome-wide characterization of human cytomegalovirus in natural infection and experimental latency

ABSTRACT: Abstract: The transcriptional program associated with herpesvirus latency and the viral genes regulating entry into and exit from latency are poorly understood and controversial. Here, we developed and validated a targeted enrichment platform and conducted large-scale transcriptome analyses of human cytomegalovirus (HCMV) infection. We used both an experimental hematopoietic cell model of latency, and cells from naturally infected, healthy human subjects (clinical) to define the breadth of viral genes expressed. The viral transcriptome derived from experimental infection was highly correlated with that from clinical infection, validating our experimental latency model. These transcriptomes revealed a broader profile of gene expression during infection in hematopoietic cells than previously appreciated. Further, using recombinant viruses that establish a non-reactivating, latent-like or replicative infection in CD34+ hematopoietic progenitors (HPCs), we defined classes of low to moderately expressed genes that are differentially regulated in latent vs. replicative states of infection. Most of these genes have yet to be studied in depth. By contrast, genes that were highly expressed, were expressed similarly in both latent and replicative infection. From these findings, a model emerges whereby low or moderately expressed genes may have the greatest impact on regulating the switch between viral latency and replication. The core set of viral genes expressed in natural infection and differentially regulated depending on the pattern of infection provides novel insight into the HCMV transcriptome associated with latency in the host and a resource for investigating new virus-host interactions underlying persistence. Significance: Herpesviruses have an extraordinarily complex relationship with their host, persisting for the lifetime of the host by way of a latent infection. Reactivation of replication is associated with significant disease risk, particularly in immunocompromised individuals. We characterize in depth transcriptional profiles of HCMV latency. We show that a broad and concordant viral transcriptome is found in both an experimental model of latency and in asymptomatically infected individuals. We further define genes that are differentially regulated during latent and replicative states- candidates for key regulators controlling the switch between latency and reactivation. This work will help understand the persistence of complex DNA viruses and provides a path towards developing antiviral strategies to control herpesvirus entry into and exit from latency.

ORGANISM(S): Human betaherpesvirus 5

PROVIDER: GSE99823 | GEO | 2017/12/04

SECONDARY ACCESSION(S): PRJNA389726

REPOSITORIES: GEO

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Project description:Latent human cytomegalovirus (HCMV) in myeloid cells can be reactivated during cell differentiation and by inflammatory mediators. Expression level of immune regulator IL1R8 has been associated with the differentiation status of myeloid cells. As far, little is known about the role of IL1R8 in the association between reactivation of latent HCMV and differentiation of myeloid cells. To gain additional insights into IL1R8 and latency, a comparative transcriptome analysis was carried out through a unique bioinformatics approach that integrated IL1R8-correlated genes with differentially expressed genes to identify IL1R8-associated significant pathways. The Metascape pathway tool was utilized to perform enrichment analysis. The initial analysis revealed a significant inverse correlation between IL1R8 and viral counts (r = -0.42, z-score = -4.69) at single cell level in HCMV-infected monocytes at 4-14 days postinfection. In contrast to the majority of pathway analysis studies presenting unilateral up- or down-regulation, the current study discovered a number of bilaterally regulated key immune pathways in both lytic and latent infections. Notably, a ~3-fold predominant downregulation of the high-level adaptive immune system pathway was followed by a modestly predominant downregulation of mid-level Lymphocyte and low-level T cell activation pathways in latent infection. More interestingly, a unilateral upregulation pattern was identified exclusively in latent infection for Myeloid leukocyte activation, differentiation, and migration, in which upregulated genes were in concord with IL1R8 negatively correlated genes. The findings in the present study provided a comprehensive view of immunological alterations and a better understanding on the potential role of IL1R8 in the association between HCMV reactivation and myeloid cell differentiation in HCMV infection. The current study, for the first time, presented unique evidence supportive of a IL1R8-associated unilateral upregulation of myeloid leukocyte pathways in latent infection.

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Transcriptome-wide characterization of human cytomegalovirus in natural infection and experimental latency

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