title: Analyses of germline, chromosomally integrated human herpesvirus 6A and B genomes indicate emergent infection and new inflammatory mediators.
abstract: Human herpesvirus-6A (HHV-6A) is rarer than HHV-6B in many infant populations. However, they are similarly prevalent as germline, chromosomally integrated genomes (ciHHV-6A/B). This integrated form affects 0.1-1 % of the human population, where potentially virus gene expression could be in every cell, although virus relationships and health effects are not clear. In a Czech/German patient cohort ciHHV-6A was more common and diverse than ciHHV-6B. Quantitative PCR, nucleotide sequencing and telomeric integration site amplification characterized ciHHV-6 in 44 German myocarditis/cardiomyopathy and Czech malignancy/inflammatory disease (MI) patients plus donors. Comparisons were made to sequences from global virus reference strains, and blood DNA from childhood-infections from Zambia (HHV-6A mainly) and Japan (HHV-6B). The MI cohort were 86 % (18/21) ciHHV-6A, the cardiac cohort 65 % (13/20) ciHHV-6B, suggesting different disease links. Reactivation was supported by findings of 1) recombination between ciHHV-6A and HHV-6B genes in 20 % (4/21) of the MI cohort; 2) expression in a patient subset, of early/late transcripts from the inflammatory mediator genes chemokine receptor U51 and chemokine U83, both identical to ciHHV-6A DNA sequences; and 3) superinfection shown by deep sequencing identifying minor virus-variants only in ciHHV-6A, which expressed transcripts, indicating virus infection reactivates latent ciHHV-6A. Half the MI cohort had more than two copies per cell, median 5.2, indicative of reactivation. Remarkably, the integrated genomes encoded the secreted-active form of virus chemokines, rare in virus from childhood-infections. This shows integrated virus genomes can contribute new human genes with links to inflammatory pathology and supports ciHHV-6A reactivation as a source for emergent infection.
authors.affiliation: Pathogen Molecular Biology Department, London School of Hygiene and Tropical Medicine, University of London, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Tweedy
authors.affiliation: Pathogen Molecular Biology Department, London School of Hygiene and Tropical Medicine, University of London, London, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Spyrou
authors.affiliation: Department of Medical Microbiology and Department of Paediatric Haematology and Oncology, 2nd Medical Faculty of Charles University and Motol University Hospital, Prague, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Hubacek
authors.affiliation: Department of Cardiology and Pneumology, Charité-University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Kuhl
authors.affiliation: Institute of Cardiac Diagnostics and Therapy (IKDT), Berlin, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Lassner
authors.affiliation: Pathogen Molecular Biology Department, London School of Hygiene and Tropical Medicine, University of London, London, UK.
authors.forename: U A
authors.initials: UA
authors.lastname: Gompels
mesh_terms: D002877:Chromosomes, Human / Q000821:virology*; D015331:Cohort Studies; D016207:Cytokines / Q000032:analysis; D018153:Czech Republic; D005854:Germ Cells / Q000821:virology*; D005858:Germany; D015654:Herpesvirus 6, Human / Q000235:genetics*; D006801:Humans; D007223:Infant; D008969:Molecular Sequence Data; D019349:Roseolovirus Infections / Q000821:virology*; D017422:Sequence Analysis, DNA; D014764:Viral Proteins / Q000032:analysis; D014775:Virus Activation
chemical_list: D016207:Cytokines; D014764:Viral Proteins