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Review
. 2020 Jul 1;12(7):714.
doi: 10.3390/v12070714.

The Role of the Human Cytomegalovirus UL133-UL138 Gene Locus in Latency and Reactivation

Luwanika Mlera  1 , Melissa Moy  2 , Kristen Maness  3 , Linh N Tran  3 , Felicia D Goodrum  1   2   3
Affiliations
Review

The Role of the Human Cytomegalovirus UL133-UL138 Gene Locus in Latency and Reactivation

Luwanika Mlera et al. Viruses. .

Abstract

Human cytomegalovirus (HCMV) latency, the means by which the virus persists indefinitely in an infected individual, is a major frontier of current research efforts in the field. Towards developing a comprehensive understanding of HCMV latency and its reactivation from latency, viral determinants of latency and reactivation and their host interactions that govern the latent state and reactivation from latency have been identified. The polycistronic UL133-UL138 locus encodes determinants of both latency and reactivation. In this review, we survey the model systems used to investigate latency and new findings from these systems. Particular focus is given to the roles of the UL133, UL135, UL136 and UL138 proteins in regulating viral latency and how their known host interactions contribute to regulating host signaling pathways towards the establishment of or exit from latency. Understanding the mechanisms underlying viral latency and reactivation is important in developing strategies to block reactivation and prevent CMV disease in immunocompromised individuals, such as transplant patients.

Keywords: DNA virus; Human cytomegalovirus; UL135; UL136; UL138; herpesvirus; latency; reactivation.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
A schematic depiction of the HCMV UL133-UL138 gene locus. The UL133-UL138 gene locus, located within the ULb’ region, is present in clinical isolates and low passage viruses but lost in serially passaged laboratory strains. The 3 major transcripts that accumulate at early times of infection or additional transcripts encoding UL136 and UL138 that accumulate at late times of infection in fibroblasts are depicted. Alternative transcription/translation initiation sites lead to at least 2 UL135, 5 UL136 and 2 UL138 isoforms. Area shaded grey indicated putative or confirmed transmembrane domains.
Figure 2
Figure 2
The UL133-138 gene locus and its effect on latency and reactivation. (A) UL138 (red) suppresses virus replication for latency and UL135 (green) is required to overcome these suppressive effects for replication and reactivation. UL136 is expressed as at least five protein isoforms. Like UL133 and UL138, UL136p23/p19 are pro-latency proteins, whereas like UL135, UL136p33 and UL136p26 favor virus replication and are required for reactivation. UL136p25 has context-dependent functions, which need to be further defined. (B) Temporal regulation of the UL133-UL138 genes. Important in this cascade is the differential kinetics of gene expression: early expression of UL135 and UL138 and the early-late expression of UL136 isoforms. Maximal UL136 expression depends on viral genome synthesis, indicating that induction of its expression may function to commit the virus to replicative state or that it mediates the transition between UL138-dominant latent and UL135-dominant replicative states. IE is an acronym for immediate early and E/L denotes early/late.
Figure 3
Figure 3
Model of UL133–UL138 virus-host interactions and signaling impacting latency and reactivation. Virus binding and entry stimulates EGFR, PI3K/AKT, and MEK/ERK signaling to set a cellular environment conducive for latency. MEK/ERK stimulates Elk-1-mediated expression of MCL-1 for survival and also downregulates pro-apoptotic Bim and Puma. In latency, the viral genome is repressed, and gene expression is restricted to very low levels. EGFR and downstream PI3K/AKT and MEK/ERK pathways are important for the establishment of latency. MEK/ERK signaling stimulates EGR-1 expression in CD34+ HPCs, which stimulates UL138 gene expression to further enforce the latent infection. UL138 regulates a number of cell surface receptors, including TNFR1, MRP1 and EGFR; the significance of these receptors and their regulation by UL138 is not completely defined, but inhibition of EGFR and its downstream pathways stimulate reactivation and replication. UL135 is expressed upon reactivation. Its interaction with the adapter proteins ABI-1 and CIN85 modulate EGFR lysosomal turnover and cytoskeleton remodeling. The question marks denote a protein function that is currently full defined in the context of latency and needs further study in that context. US28, UL7 and miR-US22 have been show to impact pathways and signaling affected by UL133-UL138. Understanding how these viral factors synergize with or anatomize UL133-UL138 modulation is an important area for future directions.
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