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. 2021 May 7;12:660901. doi: 10.3389/fmicb.2021.660901

FIGURE 4.

FIGURE 4

Many HCMV-expressed proteins and miRNAs regulate the signaling pathways known to be important for the establishment, maintanence and reactivation from latency. The initial infection of CD34+ HPCs lays the foundation for the establishment of latency. Initially, gB engagement of EGFR and the ensuing signaling is required for HCMV entry into CD34+ HPCs. This initial ligand-dependent event prepares the cell for the establishment of latency through the manipulation of host signaling pathways and regulation of viral latent gene expression. These latency gene products in turn are critical for the establishment, the maintenance of and/or reactivation from latency. For example, gene products such as UL138 and UL135 regulate viral latency and host interactions by regulating various signaling pathways [such as Egr-1 activity or PI(3)K signaling] during the establishment of and exit from latency. Other products such as the viral miRNAs miR-US5-1 and miR-UL112-3p target and down regulate IKKα and IKKβ to control inflammatory cytokine regulation (such as IL-6 and TNFα) and likely to mitigate NF-KB dependent signaling that might interfere with latency programming. Other products such as soluble UL7 are released during reactivation and through binding to the Flt-3R induces activation of the downstream PI3K/AKT and MAPK/ERK signaling pathways that in turn triggers the HPC and monocyte differentiation required for complete viral reactivation. US28, another critical latency modulator, is involved in the MEK/ERK and EGFR/PI3K signaling required for HCMV reactivation from latency, as well as playing a key role in monocyte to macrophage differentiation. In addition, a variety of viral miRNAs (such as miR-US5-1, miR-US5-2, miR-US22, and miR-UL112-3p) target cellular processes and regulate virus-mediated signaling. As examples, miR-US5-2 blocks NAB1 activity, a represser of TGFβ resulting in increased production of the TGFβ that suppresses hematopoietic events; miR-US5-2 also down regulates GAB1, thus lowering MEK/ERK signaling, as well as regulates EGR1 and UL138 expression supporting a role for miR US5-2 during reactivation. Overall these viral miRNAs, UL7, US28, UL138/135 control vital signaling pathways during the establishment, maintenance of and during reactivation from latency and are intimately involved in the differentiation of the infected CD34+ HPCs into monocytes and then into productive tissue macrophages.