Abstract
Human cytomegalovirus (HCMV) encodes 22 mature microRNAs (miRNAs), which regulate a myriad of cellular processes, including vesicular trafficking, cell cycle progression, apoptosis, and immune evasion, as well as viral gene expression. Recent evidence points to a critical role for HCMV miRNAs in mediating latency in CD34+ hematopoietic progenitor cells through modulation of cellular signaling pathways, including attenuation of TGFβ and EGFR signaling. Moreover, HCMV miRNAs can act in concert with, or in opposition to, viral proteins in regulating host cell functions. Here, we comprehensively review the studies of HCMV miRNAs in the context of latency and highlight the novel processes that are manipulated by the virus using these small non-coding RNAs.
Highlights
Human cytomegalovirus (HCMV), a prototypic member of the beta-herpesvirus family, has a large, double-stranded DNA genome of approximately 230 kbp that encodes for greater than 170 proteins, as well as numerous long and small non-coding RNAs [1,2,3].CMVs have co-evolved with their hosts over millions of years, and as such a careful balance between virus replication, viral latency, and host immune control has emerged
We comprehensively review the studies of HCMV miRNAs in the context of latency and highlight the novel processes that are manipulated by the virus using these small non-coding RNAs
Both the miRNAs and UL7 are expressed at early times post-infection of CD34+ hematopoietic progenitor cells (HPCs) [15,77] and reduce FOXO3a levels and activity to limit the induction of apoptosis [77] in this cell type (Figure 2)
Summary
Human cytomegalovirus (HCMV), a prototypic member of the beta-herpesvirus family, has a large, double-stranded DNA genome of approximately 230 kbp that encodes for greater than 170 proteins, as well as numerous long and small non-coding RNAs [1,2,3]. Over the past two decades, miRNAs have emerged as potent and cell-type-specific regulators of the host cell environment These miRNAs are small, ~22 nucleotide noncoding RNAs that post-transcriptionally regulate gene expression [29]. Alpha and gamma herpesvirus miRNAs are found clustered in viral genomic regions that are known to be expressed during latency, suggesting roles in maintaining latent infection [42,43,44,45]. Reactivation requires that the viral genome remains responsive only to appropriate reactivation cues while avoiding sub-optimal activation signals Their non-immunogenic nature, along with the ability to target potentially hundreds of different transcripts, suggests that HCMV miRNAs could be key regulators of protein expression during latency, where other viral factors may not reach the expression threshold necessary to exert their functions. HPC proliferation and hematopoiesis, along with entry into and exit from latency
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