Inherited chromosomally integrated human herpesvirus 6: regional variation in prevalence, association with angina, and identification of ancestral viral lineages in two large UK studies.
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ICR Authors
Authors
Wood, ML
Bell, AJ
Young, R
Brownlie, C
Orr, N
Campbell, A
Nichols, J
Papageorgiou, K
Lake, A
Suarez, NM
Smollett, K
Jesudason, N
Camiolo, S
Vattipally, S
Hughes, J
Brown, K
Hunter, LM
Shaw, E
Storrie, S
Stansilaus, RP
Sweeney, E
Zhu, T
Fawkes, A
Murphy, L
Tyne, W
Howard, P
Jones, ME
Tomczyk, K
Richmond, A
Wilson, JF
Clark, DA
Delles, C
Royle, N
Kerr, SM
Filipe, ADS
Davison, AJ
McConnachie, A
Swerdlow, AJ
Hayward, C
Jarrett, RF
Bell, AJ
Young, R
Brownlie, C
Orr, N
Campbell, A
Nichols, J
Papageorgiou, K
Lake, A
Suarez, NM
Smollett, K
Jesudason, N
Camiolo, S
Vattipally, S
Hughes, J
Brown, K
Hunter, LM
Shaw, E
Storrie, S
Stansilaus, RP
Sweeney, E
Zhu, T
Fawkes, A
Murphy, L
Tyne, W
Howard, P
Jones, ME
Tomczyk, K
Richmond, A
Wilson, JF
Clark, DA
Delles, C
Royle, N
Kerr, SM
Filipe, ADS
Davison, AJ
McConnachie, A
Swerdlow, AJ
Hayward, C
Jarrett, RF
Document Type
Journal Article
Date
2025-07-22
Date Accepted
2025-05-05
Abstract
Tens of millions of people worldwide have inherited chromosomally integrated human herpesvirus 6 (iciHHV-6), yet we know little about the consequences. iciHHV-6-positive individuals inherit the genome of HHV-6A or HHV-6B in the germline, and viral genomes are therefore present in every nucleated cell. To investigate the epidemiology of iciHHV-6 in the UK, almost 32,000 individuals were screened from two volunteer research studies: the family-based Generation Scotland: Scottish Family Health Study (GS:SFHS) and the Breakthrough Generations Study (BGS). iciHHV-6 prevalence in GS:SFHS was, to our knowledge, higher than that in other large studies at 2.74% (647/23,637), with an iciHHV-6B prevalence of 2.55%. Scottish participants were more likely to be iciHHV-6B-positive than English (P < 0.001), and the BGS results suggested a north-south gradient of iciHHV-6B prevalence in mainland Britain. Disease association analysis confirmed the previously reported association with angina, with an odds ratio of 1.91 (95% confidence interval, 1.29, 2.82) following adjustment for known risk factors, providing compelling evidence that iciHHV-6 contributes to the risk of a common symptom. De novo integrations were not detected within GS:SFHS pedigrees; rather, our findings indicated that three viral lineages accounted for over 95% of iciHHV-6A-positive samples, and six viral lineages accounted for 90% of iciHHV-6B-positive samples in GS:SFHS. This study demonstrates that iciHHV-6 is common in the UK, shows significant regional heterogeneity in prevalence, is not entirely harmless, and is largely derived from a relatively small number of ancestral viral lineages.IMPORTANCEHuman herpesvirus 6 (HHV-6) has the unusual ability to integrate into the host chromosome telomeres. Most of the world's population is infected by HHV-6 in early childhood, but around 1% inherit the virus as a chromosomally integrated viral genome-referred to as inherited chromosomally integrated HHV-6 (iciHHV-6). Little is known about the consequences of iciHHV-6, which has the potential to cause disease through various mechanisms. Here, we have used large cohorts to study iciHHV-6 prevalence, lineages, and phenotypic associations. We replicate a previously reported association between iciHHV-6 and angina, suggesting that iciHHV-6 is not entirely benign. We show significant variation in iciHHV-6 prevalence within the UK with almost 3% of Scottish people carrying iciHHV-6. In the first detailed analysis of viral lineages at the population level, we show that 90% of iciHHV-6 is explained by nine ancestral viral lineages. These results have important implications for future disease association analyses.
Citation
Journal of Virology, 2025, 99 (7), pp. e0216024 -
Source Title
Journal of Virology
Publisher
AMER SOC MICROBIOLOGY
ISSN
0022-538X
eISSN
1098-5514
Collections
Research Team
Clinical Cancer Epidemiol