title: Reactivation of chromosomally integrated human herpesvirus-6 by telomeric circle formation.
abstract: More than 95% of the human population is infected with human herpesvirus-6 (HHV-6) during early childhood and maintains latent HHV-6 genomes either in an extra-chromosomal form or as a chromosomally integrated HHV-6 (ciHHV-6). In addition, approximately 1% of humans are born with an inheritable form of ciHHV-6 integrated into the telomeres of chromosomes. Immunosuppression and stress conditions can reactivate latent HHV-6 replication, which is associated with clinical complications and even death. We have previously shown that Chlamydia trachomatis infection reactivates ciHHV-6 and induces the formation of extra-chromosomal viral DNA in ciHHV-6 cells. Here, we propose a model and provide experimental evidence for the mechanism of ciHHV-6 reactivation. Infection with Chlamydia induced a transient shortening of telomeric ends, which subsequently led to increased telomeric circle (t-circle) formation and incomplete reconstitution of circular viral genomes containing single viral direct repeat (DR). Correspondingly, short t-circles containing parts of the HHV-6 DR were detected in cells from individuals with genetically inherited ciHHV-6. Furthermore, telomere shortening induced in the absence of Chlamydia infection also caused circularization of ciHHV-6, supporting a t-circle based mechanism for ciHHV-6 reactivation.
authors.affiliation: Chair of Microbiology, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: Bhupesh K
authors.initials: BK
authors.lastname: Prusty
authors.affiliation: Electron Microscopy Core Facility, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: George
authors.initials: G
authors.lastname: Krohne
authors.affiliation: Chair of Microbiology, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rudel
mesh_terms: D002692:Chlamydia trachomatis / Q000472:pathogenicity / Q000821:virology; D002694:Chlamydiaceae Infections / Q000235:genetics / Q000473:pathology / Q000821:virology; D002877:Chromosomes, Human / Q000235:genetics*; D004279:DNA, Viral / Q000235:genetics*; D016679:Genome, Viral; D015654:Herpesvirus 6, Human / Q000235:genetics*; D006801:Humans; D016615:Telomere / Q000235:genetics*; D059506:Telomere Shortening / Q000235:genetics; D016662:Virus Integration / Q000235:genetics; D017735:Virus Latency / Q000235:genetics; D014779:Virus Replication / Q000235:genetics
chemical_list: D004279:DNA, Viral