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

Abstract

<jats:p>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.</jats:p>

Deciphering the Potential Coding of Human Cytomegalovirus: New Predicted Transmembrane Proteome

“…Clinical isolate VR7863 and TB40-E_UNC strains lacked a large number of genes compared to the other strains. The VR7863 strain lacked some genes with unknown functions such as UL1, UL6, UL139, UL140, US13, US15, US19 and US29 and other genes involved in immunoevasion, DNA packaging, latency or viral replication such as UL37, UL40, UL119, UL133, UL135, UL148A and US20 [ 39 , 60 , 61 , 62 , 73 , 76 , 77 , 93 , 106 ]. The TB40-E_UNC strain lacked some genes with unknown function such as UL6, UL74A, UL140, US12, US19, US29, US33A, RL8A, RL9A and RL13 and other genes involved in host immune response evasion, CMV assembly, tropism, or latency such as UL119, UL132, UL133, US2, US3 and US16 [ 73 , 75 , 95 , 96 , 102 , 104 , 118 , 119 ].…”

UL135 and UL136 Epistasis Controls Reactivation of Human Cytomegalovirus

“…While dispensable for replication in fibroblasts, these genes undoubtedly play important roles in other contexts of infection in the host (34)(35)(36)(37). We have characterized a 3.6-kb polycistronic gene locus within the ULb' region encoding four genes, UL133, UL135, UL136, and UL138, collectively referred to as the UL133-UL138 locus (19,38). On whole, the UL133-UL138 locus is suppressive to viral replication (34,35).…”

Recombinant Human Cytomegalovirus Expressing an Analog-Sensitive Kinase pUL97 as Novel Tool for Functional Analyses

“…We chose the UL133-UL138-missing backbone as one part of the rationale for our studies. The deletion of the genomic region UL133-UL138 in the chosen virus context is linked to an increased dependence of the virus on pUL97 kinase activity [ 17 , 18 , 19 , 20 ]. For reasons of a complex regulatory interference between the viral proteins that normally are expressed by this genomic region (e.g., the early regulators of ORF-UL138 proteins and others) with the pUL97 functionality, such an HCMV strain, and mutants derived from it, are expected to be particularly sensitive to any regulatory or drug-mediated impairment of pUL97.…”