Download Ruth Jarrett - The Human Herpesvirus

Inherited chromosomally-integrated human
herpesvirus 6: epidemiology and disease
associations
Ruth Jarrett
MRC-University of Glasgow Centre
for Virus Research
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?
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
HHV-6 integrates into telomeres
Direct repeat (DR)
Perfect and imperfect
telomere-like repeats
Unique region
Direct repeat (DR)
Perfect and imperfect
telomere-like repeats
Host telomere
Homologous recombination
162 kb of herpesvirus genome integrated in telomere
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
Exogenous HHV-6 infection
Inherited HHV-6 (iciHHV-6)
HHV-6
DNA
HHV-6
DNA
?
Non-heritable
Heritable
Viral
reactivation
Inflammation
Drugs
HDAC inhibitors
Sudden
telomere
shortening
Telomere fusion
Influence on
expression of
sub-telomeric
genes
Altered cellular
gene expression
Chromosomespecific
Senescence
Inherited HHV-6 (iciHHV-6)
HHV-6
DNA
Consequences of iciHHV-6?
• Viral reactivation
• Age-related disease
• Cancer
Heritable
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
Detection of iciHHV-6 in the
GS:SFHS
TaqMan screen
HHV-6 DR1/
β-globin
ddPCR
ddPCR
HHV-6B DR6
HHV-6 U7
RPP30
RPP30
If negative
ddPCR
HHV-6A DR6
TaqMan
TaqMan
HHV-6A pol
HHV-6B pol
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
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
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Nick Orr
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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