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

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)

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?

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

Drugs that can cause DRESS Ascend Media Healthcare

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)

Electron microscopy of lichen planus lesional skin reference herpes virus

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)

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

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

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

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

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

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

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

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

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?

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