1. Inherited chromosomally-integrated human herpesvirus 6: epidemiology and disease associations Ruth Jarrett MRC-University of Glasgow Centre for Virus Research

2. Human herpesvirus 6 Two distinct but closely related herpesviruses – HHV-6A and HHV-6B Most individuals are infected in early childhood Virus persists for life and can be reactivated HHV-6B more prevalent in Europe, the USA and Japan HHV-6A relatively more common in Africa?

3. HHV-6 and disease Primary infection by HHV-6B causes roseola infantum and common cause of febrile seizures Reactivation rarely problematic in immunocompetent individuals In immunosuppressed individuals reactivation is associated with encephalitis, colitis, hepatitis etc. Many other associations – mesial temporal lobe epilepsy, MS, myocarditis and cardiomyopathy, low Bayley scores – reported but not proven

4. HHV-6 integrates into telomeres Direct repeat (DR) Unique region 162 kb of herpesvirus genome integrated in telomere Homologous recombination Host telomere Perfect and imperfect telomere-like repeats Perfect and imperfect telomere-like repeats

5. Integrated HHV-6 can be excised Chromosomally integrated HHV-6 can reactivate in vivo Excised viral genomes detected in vitro Chromosomally integrated HHV-6 may be a form of latent viral infection

6. Exogenous HHV-6 infection ? Non-heritable Inherited HHV-6 (iciHHV-6) HHV-6 DNA Heritable HHV-6 DNA

7. Sudden telomere shortening Influence on expression of sub-telomeric genes Inflammation Senescence Telomere fusion Altered cellular gene expression Chromosome- specific Viral reactivation Drugs HDAC inhibitors

8. Inherited HHV-6 (iciHHV-6) HHV-6 DNA Heritable Consequences of iciHHV-6? Viral reactivation Age-related disease Cancer

9. iciHHV-6 in GS:SFHS: Aims To explore clinical relevance To determine the prevalence of iciHHV-6 in a large population-based study determine whether HHV-6A or HHV-6B To determine whether chromosomal integration is random To analyse viral evolution evidence of new integrations timing of integration events

10. Detection of iciHHV-6 in the GS:SFHS TaqMan screen HHV-6 DR1/ β-globin ddPCR HHV-6B DR6 RPP30 If negative ddPCR HHV-6A DR6 ddPCR HHV-6 U7 RPP30 TaqMan HHV-6A pol TaqMan HHV-6B pol

11. Conclusions Analysis of iciHHV-6 in the GS:SFHS has uncovered some unexpected findings Regional differences in the iciHHV-6 prevalence in the UK were detected iciHHV-6 is associated with an increased risk of some disease symptoms

12. Acknowledgements University of Glasgow CVR Adam Bell Chris Brownlie Skye Storrie Andrew Davison Rob Gifford ICAMS Christian Delles Barts Health NHS Trust Duncan Clark BGS, ICR Anthony Swerdlow Nick Orr Archie Campbell Caroline Hayward Carmen Amador Shona Kerr Pamela Linksted David J Porteous Blair H Smith Lynne Hocking Sandosh Padmanabhan Edinburgh Clinical Research Facility Lee Murphy Angie Fawkes