**6.1 The human cytomegalovirus (HCMV) miRNAs**

The HCMV have co-evolved with their hosts and encoding miRNAs that are capable regulators of cell cycle progression, viral gene expression, apoptosis and host immune response evasion (**Figure 4**). In order to maintain the latent infection, the virus attempts to maintain the hematopoietic progenitor cells (HPCs) in the dormant state. EGR-1 (Early growth response gene-1) is critical in maintenance of the HPC quiescence. miR-US22 is a HCMV miRNA that is expressed during the early infection stages or reactivation to restrict the proliferation of the HPCs. It does so by targeting the host transcription factor, EGR-1, so that the HCMV can overtake the host replication machinery for its own replication. Since viral replication is close to negligible during latency, the HCMV miR-US22 is not expressed during this state [69]. Another miRNA mechanism to limit cell proliferation during latency is the suppression of the RhoA, a regulator of the actin dynamics. miR-US25–1 targets the RhoA GTPase to disable mitosis in the cells [66, 67]. The lytic and latent infections are characterized by the abundant expression of the miRNAs, miR-US25–1, miR-UL112-3p, and miR-UL22A. Although most of the HCMV miRNAs are detected during the first 4 hours of infection, miR-UL22A, miR-UL112-3p and miR-UL148D continue to be detected post-IE infection. miR-UL112-3p targets the UL123 viral mRNA that codes for IE72 which is actively involved in viral replication and cell lysis [70] miR-UL148D targets the IE response 5 transcript to indirectly regulate the expression of the viral IE genes through the signaling transduction events induced by Cyclin-dependent kinase 1 (CDK-1) in order to promote latent HCMV infections [71]. The FOXO transcription factors are the facilitators of both mitochondria-dependent and -independent pathways for the induction of apoptosis in cells [72] miR-US5–1 and miR-UL112-3p of HCMV have known to

#### **Figure 4.**

*miRNAs in other herpesvirus infections: The figure summarizes the involvement of the various miRNAs in the different events of other herpesvirus infection. Here, we have taken the example of two herpesviruses, HCMV (navy blue) and KSHV (magenta) to show the extent of v-miRNA involvement during the viral pathogenesis. Mostly, the viral miRNAs involved in replication, latency, cell survival and immune modulation have been mentioned in the figure and are the ones widely explored.*

target a member of the FOXO family, FOXO3a [73]. The mechanism involves a downregulation of FOXO3a expression such that its pro-apoptotic functions are limited and binding to the promoter of Bcl-2-like protein 11 (Bim) is restricted. In profusely HCMV replicating cells, the IKK expression was directly constrained by the miR-US5–1 and miR-UL112-3p miRNAs of HCMV, such that production of the pro-inflammatory cytokines, IL-6 and RANTES via the NF-κB pathway was considerably suppressed [74] miR-UL148D directly targets the RANTES transcript to suppress its pro-inflammatory functions [75]. Also, miRUL112-3p directly targets MICB, an MHC I-related chain B, to indirectly repress the NK-cell killing activity so as to protect the infected cells from destruction during the lytic and preferably also during the latent HCMV infections [66, 67, 76].
