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bioRxiv · 10.1101/2021.06.07.447326

Variation in Human Herpesvirus 6B telomeric integration, excision and transmission between tissues and individuals

Wood, M. L.·Veal, C. D.·Neumann, R.·Suarez, N. M.·Nichols, J.·Parker, A. J.·Martin, D.·Romaine, S. P. R.·Codd, V.·Samani, N. J.·Voors, A. A.·Tomaszewski, M.·Flamand, L.·Davison, A. J.·Royle, N. J.
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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.

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Wood, M. L., Veal, C. D., Neumann, R., Suarez, N. M., Nichols, J., Parker, A. J., Martin, D., Romaine, S. P. R., Codd, V., Samani, N. J., Voors, A. A., Tomaszewski, M., Flamand, L., Davison, A. J., Royle, N. J.. 2021-06-08. Variation in Human Herpesvirus 6B telomeric integration, excision and transmission between tissues and individuals. https://doi.org/10.1101/2021.06.07.447326

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