Abstract
Human herpesviruses 6A and 6B (HHV-6A/6B) are ubiquitous pathogens that persist lifelong in latent form and can cause severe conditions upon reactivation. They are spread by community-acquired infection of free virus (acqHHV6A/6B) and by germline transmission of inherited chromosomally integrated HHV-6A/6B (iciHHV-6A/6B) in telomeres. We exploited a hypervariable region of the HHV-6B genome to investigate the relationship between acquired and inherited virus and revealed predominantly maternal transmission of acqHHV-6B in families. Remarkably, we demonstrate that some copies of acqHHV-6B in saliva from healthy adults gained a telomere, indicative of integration and latency, and that the frequency of viral genome excision from telomeres in iciHHV-6B carriers is surprisingly high and varies between tissues. In addition, newly formed short telomeres generated by partial viral genome release are frequently lengthened, particularly in telomerase-expressing pluripotent cells. Consequently, iciHHV-6B carriers are mosaic for different iciHHV-6B structures, including circular extra-chromosomal forms that have the potential to reactivate. Finally, we show transmission of an HHV-6B strain from an iciHHV-6B mother to her non-iciHHV-6B son. Altogether, we demonstrate that iciHHV-6B can readily transition between telomere-integrated and free virus forms.
Highlights
Human herpesviruses 6A and 6B (HHV-6A/6B; species Human betaherpesvirus 6A and59 Human betaherpesvirus 6B) are closely related viruses, sharing approximately 90% sequence identity60 (Ablashi et al, 2014)
To explore the relationship between iciHHV-6A/6B and acqHHV-6A/6B, we identified a 141 genomic marker capable of distinguishing viral strains by nested PCR and sequencing
We showed previously that iciHHV-6A/6B genomes in lymphoblastoid cell lines (LCLs) can be truncated at DRL-T2, resulting in loss of the terminal DRL and formation of a novel short telomere at the breakpoint (Huang et al, 2014; Wood & Royle, 2017)
Summary
Human herpesviruses 6A and 6B (HHV-6A/6B; species Human betaherpesvirus 6A and59 Human betaherpesvirus 6B) are closely related viruses, sharing approximately 90% sequence identity60 (Ablashi et al, 2014). 59 Human betaherpesvirus 6B) are closely related viruses, sharing approximately 90% sequence identity. Their genomes comprise a unique region (U) of approximately 140 kb flanked. 61 on each side by a direct repeat (DR) of approximately 8 kb (DRL on the left and DRR on the right). A. 62 tandem repeat reiteration is located near each end of DR. T1 at the left end consists of 1-8 kb of telomere (TTAGGG) and degenerate telomere-like repeats (Huang et al, 2014; Lindquester & Pellett, 1991; Zhang et al, 2017). T2 at the right end is much shorter and contains only (TTAGGG) repeats. HHV-6A/6B have the capacity to integrate into human
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