Molecular Determinants and the Regulation of Human Cytomegalovirus Latency and Reactivation

Abstract

Human cytomegalovirus (HCMV) is a beta herpesvirus that establishes a life-long persistence in the host, like all herpesviruses, by way of a latent infection. During latency, viral genomes are maintained in a quieted state. Virus replication can be reactivated from latency in response to changes in cellular signaling caused by stress or differentiation. The past decade has brought great insights into the molecular basis of HCMV latency. Here, we review the complex persistence of HCMV with consideration of latent reservoirs, viral determinants and their host interactions, and host signaling and the control of cellular and viral gene expression that contributes to the establishment of and reactivation from latency.

Keywords: epigenetic regulation; human cytomegalovirus; latency; reactivation; signaling; transcription factors.

Figure 1

A model of human cytomegalovirus (HCMV) infection reservoirs. An initial round of lytic replication occurs in mucosal epithelial cells following virus exposure. Circulating monocytes are infected through contact with an infected epithelial cell and induce monocyte-to-macrophage differentiation and extravasation to peripheral tissues, including the bone marrow where a latent infection is established. Upon a reactivation signal, HCMV can induce the differentiation and mobilization of latently infected CD34+ bone marrow cells. While not entirely defined, HCMV may stimulate CD34+ human progenitor cell (HPC) differentiation down a monocytic lineage with an eventual terminal differentiation state of an infected macrophage or dendritic cell. These terminally differentiated cells allow for the reseeding of epithelial cell layers within peripheral organ sites.

Figure 2

Importance of epidermal growth factor receptor (EGFR) and integrin signaling during CMV latent infection. (A) EGFR signaling is important for CMV entry, translocation to the nucleus, and to establish latency. Attenuation of EGFR signaling by the UL135 proteins or inhibitors disrupts this pattern and contributes to reactivation of CMV replication. Thickness of arrows and lines depicts strength of supporting studies; (B) In monocytes, CMV binding and entry via EGFR and integrin receptors results in changes in signaling to promote cellular survival, macrophage differentiation, and motility to promote virus dissemination in the infected host. Red T bars indicate inhibition. Green arrows indicate activation.

Figure 3

Viral regulation of cellular signaling during latency. CMV utilizes a number of viral proteins and miRNAs during latent infection to alter the signaling environment within the cell to regulate the latent infection. This model demonstrates how each viral component either inhibits (red cross) or promotes (green arrow) cellular signaling events during a latent infection. As depicted, a number of viral factors target similar pathways demonstrating their necessity in the maintenance of and reactivation from latency.

Figure 4

Diagram of cellular transcription factor binding to the HCMV major immediate early promoter (MIEP). The major immediate early core promoter, enhancer, unique region, and modulator are shown. Relative locations of binding sites for activating and repressive cellular transcription factors are shown. Repeat elements are labeled with the number of base pairs repeated in each sequence. The 18-bp repeats bind NF-κB/rel, the 19-bp repeats bind CREB/ATF, and the 21-bp repeats bind SP-1, YY1, and ERF.