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.
- Michael L Wood
- Nicola J Royle
- Nicola J Royle
- Louis Flamand
- Adriaan A Voors
- 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
© 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.
For some inducible genes, the rate and molecular mechanism of transcriptional activation depends on the prior experiences of the cell. This phenomenon, called epigenetic transcriptional memory, accelerates reactivation and requires both changes in chromatin structure and recruitment of poised RNA Polymerase II (RNAPII) to the promoter. Memory of inositol starvation in budding yeast involves a positive feedback loop between transcription factor-dependent interaction with the nuclear pore complex and histone H3 lysine 4 dimethylation (H3K4me2). While H3K4me2 is essential for recruitment of RNAPII and faster reactivation, RNAPII is not required for H3K4me2. Unlike RNAPII-dependent H3K4me2 associated with transcription, RNAPII-independent H3K4me2 requires Nup100, SET3C, the Leo1 subunit of the Paf1 complex and, upon degradation of an essential transcription factor, is inherited through multiple cell cycles. The writer of this mark (COMPASS) physically interacts with the potential reader (SET3C), suggesting a molecular mechanism for the spreading and re-incorporation of H3K4me2 following DNA replication.
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