Abstract
The mechanisms underlying human cytomegalovirus (HCMV) latency remain incompletely understood. Here, we showed that a HCMV-encoded miRNA, miR-UL148D, robustly accumulates during late stages of experimental latent HCMV infection in host cells and promotes HCMV latency by modulating the immediate early response gene 5 (IER5)-cell division cycle 25B (CDC25B) axis in host cells. miR-UL148D inhibited IER5 expression by directly targeting the three-prime untranslated region(3’UTR) of IER5 mRNA and thus rescued CDC25B expression during the establishment of viral latency. Infection with NR-1ΔmiR-UL148D, a derivative of the HCMV clinical strain NR-1 with a miR-UL148D knockout mutation, resulted in sustained induction of IER5 expression but decreased CDC25B expression in host cells. Mechanistically, we further showed that CDC25B plays an important role in suppressing HCMV IE1 and lytic gene transcription by activating cyclin-dependent kinase 1 (CDK-1). Both gain-of-function and lose-of-function assays demonstrated that miR-UL148D promotes HCMV latency by helping maintain CDC25B activity in host cells. These results provide a novel mechanism through which a HCMV miRNA regulates viral latency.
Highlights
Human cytomegalovirus (HCMV), a member of the β-herpesvirus subfamily, is a ubiquitous human virus that has infected up to 90% of the adult population worldwide [1]
HCMV achieves latent infection in hematopoietic progenitor cells by silencing HCMV immediate early (IE) genes, the activation of which serves as the initial step in HCMV
We observed that Kasumi-3 and CD34+ hematopoietic progenitor cells (HPCs) infected with HCMV virus at multiplicity of infection (MOI) of 5 maintained high viability (S1 Fig)
Summary
Human cytomegalovirus (HCMV), a member of the β-herpesvirus subfamily, is a ubiquitous human virus that has infected up to 90% of the adult population worldwide [1]. Previous evidence has suggested that various viral and cellular factors are involved in the establishment of latent HCMV infection [5,6,7,8,9,10], the mechanisms underlying this type of infection remain incompletely understood. HCMV IE gene products, especially the major IE (MIE) proteins IE1 and IE2, initiate the HCMV lytic cycle by activating the expression of a cascade of early and late viral genes [11, 12]. MIE gene silencing is critical for the establishment of viral latency. The underlying mechanism remains unclear, recent studies have shown that cellular cyclin-dependent kinase (CDK) is involved in modulating the persistence or latency of HCMV infection. How cellular CDK activity is regulated during latent HCMV infection remains unclear
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