The clinical impact of inherited chromosomally-integrated human herpesvirus 6 (iciHHV-6): a comprehensive analysis using UK Biobank

Lead Research Organisation: University of Glasgow
Department Name: MRC Centre for Virus Research


Most people are infected by human herpesvirus 6A or 6B (HHV-6A or HHV-6B) in early childhood, and the virus then persists in a small number of cells in the body for life. However, in some people the virus is acquired by a completely different route - it is inherited from their parents. In these individuals, the DNA content of the virus (the viral genome) is present in every cell in the body and is passed on to successive generations in germ cells, i.e. sperm or ova. This phenomenon is called inherited chromosomally-integrated HHV-6 or iciHHV-6 for short. Tens of millions of people worldwide have iciHHV-6, and we estimate that around 1.2% of the UK population (~750,000 individuals) is affected, but little is known of the consequences.
iciHHV-6 arises because the virus can insert its genome into structures at the ends of chromosomes called telomeres. Telomeres protect the ends of chromosomes from damage and have been likened to plastic tips at the end of shoelaces. Telomeres get shorter as people age, and shorter telomeres are associated with the development of age-related diseases. Recent studies show that iciHHV-6 genomes are sometimes released from telomeres; this causes sudden shortening of the telomere and can lead to viral reactivation with the production of infectious virus. Case studies provide evidence that viral reactivation does occur in iciHHV-6-positive people, and that release of viral genomes may play a role in the development of cancer; however, the frequency of these events is not clear. Analysis of two large cohort studies has also revealed an unexpected association between iciHHV-6 and angina-like chest pains. Thus, iciHHV-6 is not simply a fossilised viral remnant but can cause disease.
The aim of this study is to evaluate the clinical importance of iciHHV-6 by analysing samples and data from 500,000 individuals in the UK Biobank cohort. We need a study of this size to show conclusively whether, or not, iciHHV-6 has a significant effect on health. The wealth of information within UK Biobank including questionnaire data, physical measurements, linkage to electronic health records, genome-wide genetic data, and more, make this the ideal resource for investigating disease associations with iciHHV-6. We will screen DNA samples from all UK Biobank participants for iciHHV-6 and characterise the viral genomes. For most individuals, we will also determine which telomere harbours the virus, since some effects may be chromosome-specific.
We will analyse disease associations in three ways. First, we will determine whether we can detect associations with diseases that have been linked previously to HHV-6, such as Alzheimer's disease. Secondly, we will perform a large exploratory analysis to look for novel associations. Lastly, we will perform a detailed analysis of iciHHV-6 and angina, a type of chest pain caused by lack of blood flow to the heart. We will use the wide-ranging cardiovascular data in UK Biobank to find out why iciHHV-6-positive individuals are more likely to suffer from angina, and whether this has serious consequences such as progression to heart attack or dropping dead.
We will determine whether iciHHV-6 has strong associations with some diseases and whether it contributes a small increase in the risk of others. iciHHV-6 might even protect against some diseases. We will also establish whether harmful effects of iciHHV-6 are common or whether they occur only rarely. Whatever the results, the findings will provide a solid evidence base for doctors and nurses advising individuals who are iciHHV-6-positive. If we discover new associations, as anticipated, the results will potentially benefit the millions of individuals and families who have iciHHV-6 through improved diagnosis and treatment.
At the end of the study, we will return the results to the UK Biobank, so that they are available to other researchers for future studies; thus, the investigation of iciHHV-6 will continue beyond this study.

Technical Summary

Human herpesvirus 6A and 6B have the unusual ability to integrate into telomeres of human chromosomes and, in some people, viral genomes are present in the germline, giving rise to inherited chromosomally integrated HHV-6 (iciHHV-6). iciHHV-6 has the potential to cause disease through viral reactivation and by interfering with telomere function. We know that iciHHV-6 can reactivate in vivo, and analysis of two cohort studies has shown an association with an increased risk of angina. However, the overall impact of iciHHV-6 on health is not clear. We estimate that around 1.2% of the UK population is iciHHV-6-positive and it is, therefore, important to understand the health implications. A large study is required to have the power to detect associations with diseases that are not common, and associations with small effect sizes.
This study will investigate the clinical impact of iciHHV-6 through analysis of UK Biobank, a cohort with samples and data from 500,000 individuals. iciHHV-6A and 6B status will be determined using a two-stage strategy involving an initial screen of all samples using a triplex TaqMan assay, and secondary analysis of likely positive samples using droplet digital PCR. Most iciHHV-6 in the UK can be traced to a small number of ancestral viral integrations; we will use complementary approaches to identify these ancestral viral lineages as they may influence disease associations. We will test previously reported disease associations and identify new associations by analysing a wide range of physical and mental health phenotypes in an agnostic fashion. We will investigate the link between iciHHV-6 and angina and determine the consequences using the wealth of cardiovascular data in UK Biobank. Analyses will be performed for iciHHV-6 overall, and for iciHHV-6A and 6B. The findings will provide a solid evidence base for counselling individuals found to be iciHHV-6-positive and potentially lead to improved diagnostics and treatment in the future.

Planned Impact

This study aims to determine the clinical impact of inherited chromosomally integrated HHV-6 (iciHHV-6). This condition is not harmless: viral genomes can reactivate and produce infectious virus; iciHHV-6 increases risk of angina; and iciHHV-6 may interfere with the normal function of telomeres. However, the overall clinical burden of iciHHV-6 is not clear, and a large study is needed to resolve uncertainties surrounding reported disease associations. The study has several possible outcomes. We may find diseases that are strongly associated with iciHHV-6, or that iciHHV-6 contributes a small increase in the risk of several diseases, or that iciHHV-6 has little overall impact on health. Whatever the outcome, the results from this study will provide a sound knowledge base. The major beneficiaries will be the millions of individuals and families with iciHHV-6.
Currently, most individuals with iciHHV-6 are completely unaware that they have inherited this virus since iciHHV-6 is identified rarely outside research studies. However, the increasing use of high-throughput sequencing for the detection of viral infections and for whole-genome sequencing, coupled with an increasing interest in HHV-6 in the transplant setting, will lead to the detection of HHV-6 genomes in biological samples. If iciHHV-6 is diagnosed, we need to be able to provide affected individuals and their families with reliable information about this phenomenon and its implications.
Identification of diseases that are closely associated with iciHHV-6 will ultimately lead to testing for the virus, improved diagnostic accuracy, improved clinical management, and improved therapeutic options, thus benefiting iciHHV-6-positive patients. For iciHHV-6-positive families, who potentially have iciHHV-6-associated illnesses running in the family, there will be an explanation; this knowledge will allay anxiety and may lead to testing of family members and genetic counselling. Identification of iciHHV-6 as a risk factor for complex diseases may lead to improved risk factor modelling and potentially to testing for the virus. On the other hand, if we find that iciHHV-6 has little clinical impact, we will be able to provide sound advice and reassurance for individuals and families who are found to have iciHHV-6.
Identification of iciHHV-6-associated diseases will also benefit clinicians working in relevant specialities for the reasons described above. These may include clinical virologists, infectious disease physicians, cardiologists, and genetic counsellors. Introduction of more widespread testing for iciHHV-6 and the introduction of new tests into diagnostic laboratories, e.g. droplet digital PCR assays, will also have an impact on diagnostic virology laboratories. This, in turn, will impact on suppliers and manufacturers of virology test kits. Assays used in this project may be adopted by clinical virology laboratories and developed by commercial companies. If diseases associated with viral reactivation are identified, this will lead to clinical trials of antiviral agents and potentially to drug development. Trials of antiviral agents may also be used to prove that viral reactivation is involved in disease causation.
The widespread use of high-throughput sequencing will lead to the detection of HHV-6 within clinical and research samples. The knowledge base resulting from this project, and dissemination of the findings, will raise awareness of iciHHV-6 and avoid misinterpretation of iciHHV-6 as reactivation of exogenous HHV-6.
Analysis of ancestral viral lineages will provide information on population dynamics that will benefit evolutionary biologists, and be of interest to the general public.
Results of the study will be returned to UK Biobank and become part of this rich resource, ensuring that the data are available to other researchers.


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