Variation in human herpesvirus 6B telomeric integration, excision and transmission between tissues and individuals

  1. Michael L Wood
  2. Colin D Veal
  3. Rita Neumann
  4. Nicolás M Suárez
  5. Jenna Nichols
  6. Andrei J Parker
  7. Diana Martin
  8. Simon PR Romaine
  9. Veryan Codd
  10. Nilesh J Samani
  11. Adriaan A Voors
  12. Maciej Tomaszewski
  13. Louis Flamand
  14. Andrew J Davison
  15. Nicola J Royle  Is a corresponding author
  1. University of Leicester, United Kingdom
  2. MRC-University of Glasgow Centre for Virus Research, United Kingdom
  3. University of Groningen, Netherlands
  4. University of Manchester, United Kingdom
  5. Centre hospitalier de l'Université Laval, Canada

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.

Data availability

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

Author details

  1. Michael L Wood

    University of Leicester, Leicester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Colin D Veal

    University of Leicester, Leicester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9840-2512
  3. Rita Neumann

    University of Leicester, Leicester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Nicolás M Suárez

    MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Jenna Nichols

    MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Andrei J Parker

    University of Leicester, Leicester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0735-4357
  7. Diana Martin

    University of Leicester, Leicester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Simon PR Romaine

    University of Leicester, Leicester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Veryan Codd

    University of Leicester, Leicester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Nilesh J Samani

    University of Leicester, Leicester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Adriaan A Voors

    University of Groningen, Groningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  12. Maciej Tomaszewski

    University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Louis Flamand

    Department of Microbiology, Infectious Diseases and Immunology, Centre hospitalier de l'Université Laval, Québec, Canada
    Competing interests
    The authors declare that no competing interests exist.
  14. Andrew J Davison

    MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4991-9128
  15. Nicola J Royle

    University of Leicester, Leicester, United Kingdom
    For correspondence
    njr@le.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1174-6329

Funding

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.

Ethics

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).

Reviewing Editor

  1. Melanie M Brinkmann, Technische Universität Braunschweig, Germany

Publication history

  1. Received: May 17, 2021
  2. Preprint posted: June 8, 2021 (view preprint)
  3. Accepted: September 20, 2021
  4. Accepted Manuscript published: September 21, 2021 (version 1)
  5. Version of Record published: October 5, 2021 (version 2)

Copyright

© 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.

Metrics

  • 492
    Page views
  • 56
    Downloads
  • 1
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Michael L Wood
  2. Colin D Veal
  3. Rita Neumann
  4. Nicolás M Suárez
  5. Jenna Nichols
  6. Andrei J Parker
  7. Diana Martin
  8. Simon PR Romaine
  9. Veryan Codd
  10. Nilesh J Samani
  11. Adriaan A Voors
  12. Maciej Tomaszewski
  13. Louis Flamand
  14. Andrew J Davison
  15. Nicola J Royle
(2021)
Variation in human herpesvirus 6B telomeric integration, excision and transmission between tissues and individuals
eLife 10:e70452.
https://doi.org/10.7554/eLife.70452

Further reading

    1. Chromosomes and Gene Expression
    2. Genetics and Genomics
    Bethany Sump et al.
    Research Article

    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.

    1. Genetics and Genomics
    2. Neuroscience
    Alyssa J Lawler et al.
    Tools and Resources

    Recent discoveries of extreme cellular diversity in the brain warrant rapid development of technologies to access specific cell populations within heterogeneous tissue. Available approaches for engineering-targeted technologies for new neuron subtypes are low yield, involving intensive transgenic strain or virus screening. Here, we present Specific Nuclear-Anchored Independent Labeling (SNAIL), an improved virus-based strategy for cell labeling and nuclear isolation from heterogeneous tissue. SNAIL works by leveraging machine learning and other computational approaches to identify DNA sequence features that confer cell type-specific gene activation and then make a probe that drives an affinity purification-compatible reporter gene. As a proof of concept, we designed and validated two novel SNAIL probes that target parvalbumin-expressing (PV+) neurons. Nuclear isolation using SNAIL in wild-type mice is sufficient to capture characteristic open chromatin features of PV+ neurons in the cortex, striatum, and external globus pallidus. The SNAIL framework also has high utility for multispecies cell probe engineering; expression from a mouse PV+ SNAIL enhancer sequence was enriched in PV+ neurons of the macaque cortex. Expansion of this technology has broad applications in cell type-specific observation, manipulation, and therapeutics across species and disease models.