Variation in human herpesvirus 6B telomeric integration, excision and transmission between tissues and individuals
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.
Sequencing data have been deposited in GenBank under accession numbers: MW049313-MW049327.The HHV6 explorer is freely available at https://www.hhv6explorer.org/ and so The source code for the HHV6 explorer and HHV6 counter are available at https://github.com/colinveal/HHV6-Explorer.Other data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Biotechnology and Biological Sciences Research Council (MIBTP 1645656)
- Michael L Wood
Medical Research Council (G0901657)
- Nicola J Royle
HHV-6 Foundation (Pilot grant)
- Nicola J Royle
Canadian Institutes of Health Research (MOP 123214)
- Louis Flamand
European Commission (FP7-242209- BIOSTAT-CHF)
- Adriaan A Voors
Medical Research Council (MC_UU_12014/3)
- Andrew J Davison
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Human subjects: The study was conducted in accordance with the Declaration of Helsinki and with approval by the relevant ethics committees as follows:The University of Leicester's Research Ethics Committee (refs: 10553-njr-genetics; njr-61d3).The BIOSTAT-CHF study was approved by the relevant ethics committee in each centre, all participants gave their written, informed consent to participate (Voors et al, 2016).
- Melanie M Brinkmann, Technische Universität Braunschweig, Germany
- Received: May 17, 2021
- Preprint posted: June 8, 2021 (view preprint)
- Accepted: September 20, 2021
- Accepted Manuscript published: September 21, 2021 (version 1)
- Version of Record published: October 5, 2021 (version 2)
© 2021, Wood et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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