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J Gen Virol. 2015 Feb;96(Pt 2):370-89. doi: 10.1099/vir.0.068536-0. Epub 2014 Oct 29.

Analyses of germline, chromosomally integrated human herpesvirus 6A and B genomes indicate emergent infection and new inflammatory mediators.

Author information

1
Pathogen Molecular Biology Department, London School of Hygiene and Tropical Medicine, University of London, London, UK.
2
Department of Medical Microbiology and Department of Paediatric Haematology and Oncology, 2nd Medical Faculty of Charles University and Motol University Hospital, Prague, Czech Republic.
3
Department of Cardiology and Pneumology, Charité-University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.
4
Institute of Cardiac Diagnostics and Therapy (IKDT), Berlin, Germany.
5
Pathogen Molecular Biology Department, London School of Hygiene and Tropical Medicine, University of London, London, UK Ursula.gompels@lshtm.ac.uk.

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.

PMID:
25355130
DOI:
10.1099/vir.0.068536-0
[Indexed for MEDLINE]

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