Cytomegalovirus latency and reactivation: recent insights into an age old problem

Abstract

Human cytomegalovirus (HCMV) infection remains a major cause of morbidity in patient populations. In certain clinical settings, it is the reactivation of the pre-existing latent infection in the host that poses the health risk. The prevailing view of HCMV latency was that the virus was essentially quiescent in myeloid progenitor cells and that terminal differentiation resulted in the initiation of the lytic lifecycle and reactivation of infectious virus. However, our understanding of HCMV latency and reactivation at the molecular level has been greatly enhanced through recent advancements in systems biology approaches to perform global analyses of both experimental and natural latency. These approaches, in concert with more classical reductionist experimentation, are furnishing researchers with new concepts in cytomegalovirus latency and suggest that latent infection is far more active than first thought. In this review, we will focus on new studies that suggest that distinct sites of cellular latency could exist in the human host, which, when coupled with recent observations that report different transcriptional programmes within cells of the myeloid lineage, argues for multiple latent phenotypes that could impact differently on the biology of this virus in vivo. Finally, we will also consider how the biology of the host cell where the latent infection persists further contributes to the concept of a spectrum of latent phenotypes in multiple cell types that can be exploited by the virus.

Figure 1. Human cytomegalovirus natural latency in cell lineages.

Viral latency is established in the haematopoietic progenitors resident in the bone marrow and the carriage of viral genomes has been defined in the monocyte/myeloid lineage with reactivation occurring in the terminally differentiated myeloid macrophages and DCs (Orange cells). In contrast, the viral genome is not carried in the lymphocyte population nor is there any evidence for viral latency in venous endothelial cells (grey cells). Experimental infection data suggest that endothelial and neuronal progenitor cells may also be sites of latency although no data from natural latency currently exists (blue cells).

Figure 2. Chromatin mediated regulation of viral immediate early gene expression during latency.

The MIEP is bound by methylated histones and additional repressor complexes including HP1 and PRC2. The mechanism of HP1 recruitment is unknown but likely occurs through a high affinity interaction with histone H3 methylated at residue lysine 9. The recruitment of PRC2 is directed by the viral lnc4.9 transcript which promotes extensive histone methylation of lysine residue 27 of histone H3. Multiple chromatin states could exist where individual MIEPs are either bound exclusively by HP1 (a) or PRC2 (b), or the MIEP could be regulated by both marks concomitantly (c). The differing functions of PRC2 in the establishment of repressive chromatin and HP1 in the long term maintenance of silenced chromatin may point towards specific roles at different times during latent infection.

Figure 3. Signal integration is required to trigger viral reactivation.

HCMV reactivation has been reported to be ERK-MAPK dependent in DCs stimulated with IL-6. The targeting of ERK-MAPK activity to the MIEP in DCs likely involves the activation of multiple pathways to generate the specific output required. Multiple mechanisms could be responsible including the activation of additional IL-6 responsive pathways or the activation of additional pathways via concomitant binding of additional ligands.