Abstract
Sequences homologous to human herpesvirus 6 (HHV-6) are integrated within the nuclear genome of about 1% of humans, but it is not clear how this came about. It is also uncertain whether integrated HHV-6 can reactivate into an infectious virus. HHV-6 integrates into telomeres, and this has recently been associated with polymorphisms affecting MOV10L1. MOV10L1 is located on the subtelomere of chromosome 22q (chr22q) and is required to make PIWI-interacting RNAs (piRNAs). As piRNAs block germline integration of transposons, piRNA-mediated repression of HHV-6 integration has been proposed to explain this association. In vitro, recombination of the HHV-6 genome along its terminal direct repeats (DRs) leads to excision from the telomere and viral reactivation, but the expected “solo-DR scar” has not been described in vivo. Here we screened for integrated HHV-6 in 7,485 Japanese subjects using whole-genome sequencing (WGS). Integrated HHV-6 was associated with polymorphisms on chr22q. However, in contrast to prior work, we find that the reported MOV10L1 polymorphism is physically linked to an ancient endogenous HHV-6A variant integrated into the telomere of chr22q in East Asians. Unexpectedly, an HHV-6B variant has also endogenized in chr22q; two endogenous HHV-6 variants at this locus thus account for 72% of all integrated HHV-6 in Japan. We also report human genomes carrying only one portion of the HHV-6B genome, a solo-DR, supporting in vivo excision and possible viral reactivation. Together these results explain the recently-reported association between integrated HHV-6 and MOV10L1/piRNAs, suggest potential exaptation of HHV-6 in its coevolution with human chr22q, and clarify the evolution and risk of reactivation of the only intact (non-retro)viral genome known to be present in human germlines.
Highlights
human herpesvirus 6 (HHV-6) are betaherpesviruses and consist of two recently distinguished species, HHV-6A and HHV-6B, whose genomes share 90% nucleotide identity [1]
Human herpesvirus 6 (HHV-6) infects most people during childhood and can reactivate later in life to contribute to diseases
Little is known about how HHV-6 genomes entered human genomes, whether or not they still do, and the risk this poses for virus reactivation
Summary
HHV-6 are betaherpesviruses and consist of two recently distinguished species, HHV-6A and HHV-6B, whose genomes share 90% nucleotide identity [1]. HHV-6 are members of the Roseolavirus genus, named after roseola, the clinical syndrome of fever and rash caused by primary infection by these viruses. Most people are infected with HHV-6 as infants. HHV-6B is most often responsible for primary HHV-6 infection in regions where identification of the responsible species has been performed. Primary HHV-6 infection can lead to central nervous system disease including febrile status epilepticus [2]. HHV-6 viremia occurs in about 40% of immunosuppressed transplant recipients, in whom it can cause severe complications, including limbic encephalitis [3]. HHV-6 have been associated with other neurological diseases including multiple sclerosis (reviewed in [4]) and Alzheimer’s disease [5]. HHV-6 can establish presumably life-long, latent infection. In contrast to other herpesviruses, this may require integration of the viral genome into the host chromosome [6]
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