Abstract
Human cytomegalovirus (HCMV) latency and reactivation is regulated by the chromatin structure at the major immediate early promoter (MIEP) within myeloid cells. Both cellular and viral factors are known to control this promoter during latency, here we will review the known mechanisms for MIEP regulation during latency. We will then focus on the virally encoded G-protein coupled receptor, US28, which suppresses the MIEP in early myeloid lineage cells. The importance of this function is underlined by the fact that US28 is essential for HCMV latency in CD34+ progenitor cells and CD14+ monocytes. We will describe cellular signalling pathways modulated by US28 to direct MIEP suppression during latency and demonstrate how US28 is able to ‘regulate the regulators’ of HCMV latency. Finally, we will describe how cell-surface US28 can be a target for antiviral therapies directed at the latent viral reservoir.
Highlights
Human cytomegalovirus (HCMV) persists for the lifetime of the host, a process underpinned by the establishment of latency in specific cell types
Sporadic reactivation of HCMV is thought to be well-controlled by host immune responses resulting in subclinical events, but HCMV reactivation poses a grave risk to immunocompromised individuals, especially immunosuppressed organ transplant recipients
HCMV latency and reactivation is regulated by chromatin structure at the major immediate early promoter
Summary
Human cytomegalovirus (HCMV) persists for the lifetime of the host, a process underpinned by the establishment of latency in specific cell types. A repressive chromatin structure around the MIEP must be established during latency in myeloid progenitors and modified during reactivation to permit efficient IE gene expression in differentiated dendritic cells and macrophages (Fig. 1) We know that this process relies upon both cellular and viral factors; these can function by direct binding to the MIEP or by indirect mechanisms and have either activatory or repressive functions. A key mechanism by which US28 supports latency in undifferentiated myeloid cells is to modulate multiple cellular signalling pathways, which alters the balance of activatory and repressive factors at the MIEP, the result of which is to promote a repressive chromatin structure at the MIEP and suppress IE gene expression. Several groups are developing alternative US28 inhibitors [75–77] which might provide a highly-selective US28-based shock and kill strategy in the transplant setting
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