title: Complete Genome Sequence of Germline Chromosomally Integrated Human Herpesvirus 6A and Analyses Integration Sites Define a New Human Endogenous Virus with Potential to Reactivate as an Emerging Infection.
abstract: Human herpesvirus-6A and B (HHV-6A, HHV-6B) have recently defined endogenous genomes, resulting from integration into the germline: chromosomally-integrated "CiHHV-6A/B". These affect approximately 1.0% of human populations, giving potential for virus gene expression in every cell. We previously showed that CiHHV-6A was more divergent than CiHHV-6B by examining four genes in 44 European CiHHV-6A/B cardiac/haematology patients. There was evidence for gene expression/reactivation, implying functional non-defective genomes. To further define the relationship between HHV-6A and CiHHV-6A we used next-generation sequencing to characterize genomes from three CiHHV-6A cardiac patients. Comparisons to known exogenous HHV-6A showed CiHHV-6A genomes formed a separate clade; including all 85 non-interrupted genes and necessary cis-acting signals for reactivation as infectious virus. Greater single nucleotide polymorphism (SNP) density was defined in 16 genes and the direct repeats (DR) terminal regions. Using these SNPs, deep sequencing analyses demonstrated superinfection with exogenous HHV-6A in two of the CiHHV-6A patients with recurrent cardiac disease. Characterisation of the integration sites in twelve patients identified the human chromosome 17p subtelomere as a prevalent site, which had specific repeat structures and phylogenetically related CiHHV-6A coding sequences indicating common ancestral origins. Overall CiHHV-6A genomes were similar, but distinct from known exogenous HHV-6A virus, and have the capacity to reactivate as emerging virus infections.
authors.affiliation: Department of Pathogen Molecular Biology, London School of Hygiene & Tropical Medicine, University of London, London WC1E 7HT, UK. joshua.tweedy@lshtm.ac.uk.
authors.forename: Joshua
authors.initials: J
authors.lastname: Tweedy
authors.affiliation: Department of Pathogen Molecular Biology, London School of Hygiene & Tropical Medicine, University of London, London WC1E 7HT, UK. maria-alexandra.spyrou@lshtm.ac.uk.
authors.forename: Maria Alexandra
authors.initials: MA
authors.lastname: Spyrou
authors.affiliation: Department of Pathogen Molecular Biology, London School of Hygiene & Tropical Medicine, University of London, London WC1E 7HT, UK. max.pearson@lshtm.ac.uk.
authors.forename: Max
authors.initials: M
authors.lastname: Pearson
authors.affiliation: Institute of Cardiac diagnostics (IKDT), Charite University, D-12203 Berlin, Germany. info@ikdt.de.
authors.forename: Dirk
authors.initials: D
authors.lastname: Lassner
authors.affiliation: Institute of Cardiac diagnostics (IKDT), Charite University, D-12203 Berlin, Germany. infom@IKDT.de.
authors.forename: Uwe
authors.initials: U
authors.lastname: Kuhl
authors.affiliation: Department of Pathogen Molecular Biology, London School of Hygiene & Tropical Medicine, University of London, London WC1E 7HT, UK. ursula.gompels@lshtm.ac.uk.
authors.forename: Ursula A
authors.initials: UA
authors.lastname: Gompels
mesh_terms: D001483:Base Sequence; D002877:Chromosomes, Human / Q000235:genetics / Q000821:virology*; D006333:Heart Failure / Q000235:genetics / Q000821:virology*; D015654:Herpesvirus 6, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D010802:Phylogeny; D011446:Prospective Studies; D019349:Roseolovirus Infections / Q000235:genetics / Q000821:virology*; D016662:Virus Integration
keywords: CiHHV-6; CiHHV-6A; HHV-6; HHV-6A; chromosomal integration; human herpesvirus; subtelomere; telomeric repeats; virus genome