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.
Highlights
For human herpesviruses, both human herpesvirus 6A and B, HHV-6A and HHV-6B, have forms integrated into the germline of human chromosomes in approximately 1% of human populations examined [1,2,3,4]
Results were separated into CiHHV-6A and CiHHV-6B, showing 0.2% and 0.4% respectively, in screens of over 19,000 individuals identifying 115 with CiHHV-6A or B
Our previous studies showed European CiHHV-6A sequences were more divergent than CiHHV-6B suggesting earlier origins [21]
Summary
For human herpesviruses, both human herpesvirus 6A and B, HHV-6A and HHV-6B, have forms integrated into the germline of human chromosomes in approximately 1% of human populations examined [1,2,3,4]. This integration involves homologous recombination between common. Since integrated genomes are present in every nucleated cell, quantification by real time DNA. If the genomes are intact, there could be gene expression from over 85 viral genes in each cell as well as the potential for reactivated infectious virus [6,7]. Ramifications for health are beginning to be evaluated and crucial to this is an understanding of the relationship between exogenous HHV-6 virus and germline-integrated CiHHV-6 genomes
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