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Viruses. 2016 Jan 15;8(1). pii: E19. doi: 10.3390/v8010019.

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.

Author information

1
Department of Pathogen Molecular Biology, London School of Hygiene & Tropical Medicine, University of London, London WC1E 7HT, UK. joshua.tweedy@lshtm.ac.uk.
2
Department of Pathogen Molecular Biology, London School of Hygiene & Tropical Medicine, University of London, London WC1E 7HT, UK. maria-alexandra.spyrou@lshtm.ac.uk.
3
Department of Pathogen Molecular Biology, London School of Hygiene & Tropical Medicine, University of London, London WC1E 7HT, UK. max.pearson@lshtm.ac.uk.
4
Institute of Cardiac diagnostics (IKDT), Charite University, D-12203 Berlin, Germany. info@ikdt.de.
5
Institute of Cardiac diagnostics (IKDT), Charite University, D-12203 Berlin, Germany. infom@IKDT.de.
6
Department of Pathogen Molecular Biology, London School of Hygiene & Tropical Medicine, University of London, London WC1E 7HT, UK. ursula.gompels@lshtm.ac.uk.

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.

KEYWORDS:

CiHHV-6; CiHHV-6A; HHV-6; HHV-6A; chromosomal integration; human herpesvirus; subtelomere; telomeric repeats; virus genome

PMID:
26784220
PMCID:
PMC4728579
DOI:
10.3390/v8010019
[Indexed for MEDLINE]
Free PMC Article

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