title: Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Κb activation.
abstract: Epstein-Barr virus (EBV) is associated with several types of cancers including Hodgkin's lymphoma (HL) and nasopharyngeal carcinoma (NPC). EBV-encoded latent membrane protein 1 (LMP1), a multifunctional oncoprotein, is a powerful activator of the transcription factor NF-κB, a property that is essential for EBV-transformed lymphoblastoid cell survival. Previous studies reported LMP1 sequence variations and induction of higher NF-κB activation levels compared to the prototype B95-8 LMP1 by some variants. Here we used biopsies of EBV-associated cancers and blood of individuals included in the Swiss HIV Cohort Study (SHCS) to analyze LMP1 genetic diversity and impact of sequence variations on LMP1-mediated NF-κB activation potential. We found that a number of variants mediate higher NF-κB activation levels when compared to B95-8 LMP1 and mapped three single polymorphisms responsible for this phenotype: F106Y, I124V and F144I. F106Y was present in all LMP1 isolated in this study and its effect was variant dependent, suggesting that it was modulated by other polymorphisms. The two polymorphisms I124V and F144I were present in distinct phylogenetic groups and were linked with other specific polymorphisms nearby, I152L and D150A/L151I, respectively. The two sets of polymorphisms, I124V/I152L and F144I/D150A/L151I, which were markers of increased NF-κB activation in vitro, were not associated with EBV-associated HL in the SHCS. Taken together these results highlighted the importance of single polymorphisms for the modulation of LMP1 signaling activity and demonstrated that several groups of LMP1 variants, through distinct mutational paths, mediated enhanced NF-κB activation levels compared to B95-8 LMP1.
authors.affiliation: Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Emilie
authors.initials: E
authors.lastname: Zuercher
authors.forename: Christophe
authors.initials: C
authors.lastname: Butticaz
authors.forename: Josiane
authors.initials: J
authors.lastname: Wyniger
authors.forename: Raquel
authors.initials: R
authors.lastname: Martinez
authors.forename: Manuel
authors.initials: M
authors.lastname: Battegay
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Boffi El Amari
authors.forename: Thanh
authors.initials: T
authors.lastname: Dang
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Egger
authors.forename: Jan
authors.initials: J
authors.lastname: Fehr
authors.forename: Esther
authors.initials: E
authors.lastname: Mueller-Garamvögyi
authors.forename: Andrea
authors.initials: A
authors.lastname: Parini
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Schaefer
authors.forename: Franziska
authors.initials: F
authors.lastname: Schoeni-Affolter
authors.forename: Christine
authors.initials: C
authors.lastname: Thurnheer
authors.forename: Marianne
authors.initials: M
authors.lastname: Tinguely
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
authors.forename: Sylvia
authors.initials: S
authors.lastname: Rothenberger
mesh_terms: D002470:Cell Survival; D002472:Cell Transformation, Viral / Q000235:genetics; D004252:DNA Mutational Analysis; D014644:Genetic Variation; D015658:HIV Infections / Q000821:virology*; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D008214:Lymphocytes / Q000821:virology; D008954:Models, Biological; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D010802:Phylogeny; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D014763:Viral Matrix Proteins / Q000378:metabolism
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D014763:Viral Matrix Proteins