1. What is new on HHV 6, 7, 8 infections?
Henry J.C. de Vries
Dermatology
Academic Medical Centre
University of Amsterdam
The Netherlands

2. HHV 6 and 7 Acute/primary infection
Until 1986, 5 herpes viruses
new human herpes viruses (HHV)
HHV-6 and -7
both members of the Roseolovirus genus of the β- herpesviruses.
T-lymphotropic but can infect other cell types
primary infections are associated with roseola infantum (a.k.a. exanthem subitum or 6th disease)

3. HHV 6 and 7 Reactivation/endogenous infection
HHV lifetime infection
ubiquitous
reactivation
HHV-7 and HHV-6 reactivation associated with pityriasis rosea (Drago, 1997 and Yasukawa, 1999)
Debated
Innocent bystander?
Multiple agents?

4. DRESS syndrome
Drug Reaction Eosinophilia and Systemic side effect Syndrome (DRESS)
HHV 6 reactivation (Deschamps 2001)
exanthema,hepatitis, colitis lymphadenopathy, eosinophilia, fever
EBV and amoxicillin associated drug rash in mononucleosis infectiosa
C Goldberg, UCSD and
Ascend Media Healthcare

5. Drugs that can cause DRESS
Ascend Media Healthcare

6. Is lichen planus caused by a viral infection?
Highest prevalence in over 50 year olds
Self limiting
Normally one episode
Association with HCV (Mokni 1991)
The epidemiological association is not strong (Imhof, 1997)

7. Electron microscopy of lichen planus lesional skin
reference herpes virus

8. Study outline Objective: Methods:
To find candidate herpes viruses associated with lichen planus.
Methods:
Lichen planus patients (pathologically confirmed, n=18)
Intra patient comparison of skin biopsies:
lesional vs. non-lesional
before vs. after remission
Inter patient comparison of skin biopsies:
psoriasis patients (lesional, n=11, and non-lesional, n=3)
normal skin (redundant after breast reduction, n=4)
DNA of HSV1 and 2, VZV, CMV, EBV (commercial PCR )
DNA of HHV 6, -7 and -8 (“in house” nested PCR)

9. Herpes DNA analysis HHV7 HHV6 Lichen planus lesional non-lesional PBMC
All samples were free of HSV-1, HSV-2, VZV, CMV and HHV-8 DNA.
EBV DNA was detected in 2/15 lichen planus lesional samples.
HHV7
HHV6
Lichen planus
lesional
non-lesional
PBMC
11/18 (61%)*,#
1/11 (9%)*
5/13 (38%)
0/18 (0%)
0/11 (0%)
2/13 (15%)
Psoriasis
2/11 (18%)#
0/3 (0%)
1/11 (9%)
0/3 (0%)
Normal skin
0/4 (0%)
0/4 (0%)
* p=0,06, # p=0,05 p values calculated with McNemar test

10. HHV-7 protein in lesional lichen planus
Immunohistochemical detection viral protein (HHV-7)
tegument protein pp85 (Advanced Biotechnologies)
positive cells/mm2
(non) lesional lichen planus, psoriasis, normal skin
lesional skin non-lesional skin
de Vries et al. Br J Dermatol 154: 361, 2006

11. HHV-7 protein positive cells
psoriasis lesional lichen planus
normal skin non lesional lichen planus -
de Vries et al. Br J Dermatol 154: 361, 2006

12. lesional skin non-lesional skin
plasmacytoid dendritic cells (CD123+) associated with viral infection in lesional lichen planus
lesional skin non-lesional skin
CD123 positive cells(red), endothelial cells (blue)
de Vries et al. Br J Dermatol 154: 361, 2006

13. HHV-7 replicates in plasmacytoid dendritic (BDCA-2+) cells
lesional lichen planus
lesional lichen planus
HHV-7/BDCA-2 double staining
HHV-7/CD-3 double staining
de Vries et al. Arch Dermatol Res 299: 213, 2007

14. HHV-7 DNA and protein positive cells before and after lichen planus remission
before treatment after remission
de Vries et al. Arch Dermatol Res 299: 213, 2007

15. Conclusions
herpes virus like particles reside in lesional lichen planus skin
not HSV1, HSV2, CMV, VZV, HHV6 or HHV8 DNA
HHV-7 replicates in lesional lichen planus,
not in non-lesional lichen planus, psoriatic or normal skin
HHV-7 replicates in plasmacytoid dendritic cells
HHV-7 replication in lichen planus stops after remission

16. HHV-7 and lichen planus hypothesis
HHV-7 (subclinical) primo infection during childhood
HHV-7 reactivation in adult life
replication in basal keratinocytes/dermal lymphocytes
presentation (plasmacytoid) dendritic cells
inflammatory T lymphocytic response
destruction of the basal layer
Skin Immune System, Bos JD ed. 3rd edition, 2005

17. How to prove a causative viral association?
viral “innocent bystander”
Koch’s postulates
geographic variation in viral distribution
differences in laboratory protocols
virus-virus interactions
association with skin diseases?
or candidates in search of a disease?

18. Acknowledgement Jan van Marle Jan Weel
electronmicroscopy
Jan Weel
virology
Fokla Zorgdrager and Marion Cornelissen
molecular biology
Daisy Picavet and Marcel Teunissen
immunohistochemistry