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. 2016 Sep 29;3(1):333-357.
doi: 10.1146/annurev-virology-110615-042422. Epub 2016 Aug 4.

Human Cytomegalovirus Latency: Approaching the Gordian Knot

Felicia Goodrum  1
Affiliations

Human Cytomegalovirus Latency: Approaching the Gordian Knot

Felicia Goodrum. Annu Rev Virol. .

Abstract

Herpesviruses have evolved exquisite virus-host interactions that co-opt or evade a number of host pathways to enable the viruses to persist. Persistence of human cytomegalovirus (CMV), the prototypical betaherpesvirus, is particularly complex in the host organism. Depending on host physiology and the cell types infected, CMV persistence comprises latent, chronic, and productive states that may occur concurrently. Viral latency is a central strategy by which herpesviruses ensure their lifelong persistence. Although much remains to be defined about the virus-host interactions important to CMV latency, it is clear that checkpoints composed of viral and cellular factors exist to either maintain a latent state or initiate productive replication in response to host cues. CMV offers a rich platform for defining the virus-host interactions and understanding the host biology important to viral latency. This review describes current understanding of the virus-host interactions that contribute to viral latency and reactivation.

Keywords: EGFR; ULb′; cytomegalovirus; herpesvirus; latency; signaling.

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Figures

Figure 1
Figure 1. Schematic of CMV latency
Following entry into the cell and delivery of the genome (green circle) to the nucleus, cell type-specific i defenses, the activity of viral tegument proteins, and as yet undefined virus-host interactions begin to define the pattern of infection: productive, chronic, or latent. Cellular differentiation and other host cues can reactivate virus replication. In productive states of replication, all three classes of viral transcripts are expressed. The transcriptome associated with viral latency is more poorly defined.
Figure 2
Figure 2. The Gordian knot
CMV latency is a complex and poorly understood process that is controlled by (i) viral factors, (ii) cell type-specific factors in the infected cell, and (iii) innate and adaptive host responses. These three aspects of CMV persistence are inextricably linked. Untangling the knot will require an integrated inquiry into these facets of latency.
Figure 3
Figure 3. The CMV genome, UL/b’, and UL133/8 locus
Low-passage strains retain a ~15-kb region of the genome termed UL/b’ that is lost during the serial passage of the virus in fibroblasts. The UL/b’ region encodes 19–20 ORFs, many of which have no defined function. The UL133/8 locus coordinates the expression of 4 genes from a series of polycistronic transcripts. The UL133/8 proteins have roles in latency and reactivation in CD34+ HPCs, as well as for replication in endothelial cells.
Figure 4
Figure 4. A model for synergistic and antagonistic interactions between UL133/8 proteins in regulating latency
UL133 and UL138 promote viral latency. UL138-mediated suppression of virus replication is overcome in part by replication-promoting activity of UL135 for reactivation. UL136 isoforms synergize and antagonize one another in regulating the level of virus replication in CD34+ HPCs. The UL136 33- and 26-kDa isoforms promote replication and are required for replication, whereas the 23- and 19-kDa isoforms suppress replication. The 25-kDa isoform has context-dependent roles. The 25-kDa isoform promotes the maintenance of latency in CD34+ HPCs, but is also required for reactivation or dissemination in humanized mice.
Figure 5
Figure 5. UL135 and UL138 antagonistically regulate EGFR surface levels and trafficking
During CMV infection in fibroblasts, EGFR is sequestered in an activated form at the vAC. UL138 enhances recycling of EGFR to sustain cell surface levels, while UL135 promotes EGFR turnover. EGFR, together with UL135 and UL138, constitute a molecular switch controlling latency. EGFR and downstream PI3K signaling sustain latency. The mechanisms by which UL135 and UL138 regulate EGFR trafficking are not defined.
Figure 6
Figure 6. A model of virus-host interactions underlying latency
CMV latency requires coordinated regulation of viral gene expression, maintenance of the viral genome, and modulation of host processes and responses. Virus entry stimulates EGFR and induces Mcl-1 in monocytes—events that enhance cellular motility and survival. The viral genome is chromatinized upon delivery to the nucleus. Viral transcription is restricted by host epigenetic modulators and virus factors, but the mechanisms are not completely defined. While the latent transcriptome is not well understood, expression of a number of viral genes has been detected and their roles in regulating viral gene expression or host responses are beginning to be defined. Thematically, many CMV latency determinants regulate host signaling as a means by which to control differentiation, survival, and detection by the immune response. The mechanisms by which viral factors regulate host signaling and the effect of these interactions on patterns of infection in various cell types remains to be fully understood.
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