title: Mechanisms that regulate Epstein-Barr virus EBNA-1 gene transcription during restricted latency are conserved among lymphocryptoviruses of Old World primates.
abstract: Epstein-Barr virus (EBV), the only known human lymphocryptovirus (LCV), displays a remarkable degree of genetic and biologic identity to LCVs that infect Old World primates. Within their natural hosts, infection by these viruses recapitulates many key aspects of EBV infection, including the establishment of long-term latency within B lymphocytes, and is therefore a potentially valuable animal model of EBV infection. However, it is unclear whether these LCVs have adopted or maintained the same mechanisms used by EBV to express essential viral proteins, such as EBNA-1, in the face of cell-mediated repression of EBV gene expression that occurs upon establishment of the asymptomatic carrier state. To address this issue, we determined whether the endogenous LCVs of baboon (Cercopithecine herpesvirus 12) and rhesus macaque (Cercopithecine herpesvirus 15) have the functional equivalent of the EBV promoter Qp, which mediates exclusive expression of EBNA-1 during the restricted programs of EBV latency associated with the carrier state. Our results indicate that (i) both the baboon and rhesus macaque LCVs have a genomic locus that is highly homologous to the EBV Qp region, (ii) key cis-regulatory elements of Qp are conserved in these LCV genomes and compose promoters that are functionally indistinguishable from EBV Qp, and (iii) EBNA-1 transcripts identical in structure to EBV Qp-specific EBNA-1 mRNAs are present in nonhuman LCV-infected cells, demonstrating that these Qp homologs are indeed utilized as alternative EBNA-1 promoters. These observations indicate that the molecular mechanisms which regulate EBV gene expression during restricted latency have been conserved among the LCVs. The contribution of these mechanisms to viral persistence in vivo can now be experimentally tested in nonhuman primate models of LCV infection.
authors.affiliation: Program in Viral Oncogenesis and Tumor Immunology, Department of Virology and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: I K
authors.initials: IK
authors.lastname: Ruf
authors.forename: A
authors.initials: A
authors.lastname: Moghaddam
authors.forename: F
authors.initials: F
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Sample
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000821:virology; D001483:Base Sequence; D002478:Cells, Cultured; D004279:DNA, Viral / Q000737:chemistry; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics*; D006706:Homeostasis; D018143:Lymphocryptovirus / Q000235:genetics*; D008969:Molecular Sequence Data; D010215:Papio; D011401:Promoter Regions, Genetic; D016385:TATA Box; D014158:Transcription, Genetic; D017735:Virus Latency