The HHV6 paradox: ubiquitous commensal or insidious pathogen? A two-step in situ PCR approach.
BACKGROUND
Progressive multifocal leukoencephalopathy (PML) and multiple sclerosis (MS) are demyelinative diseases of the central nervous system (CNS). PML occurs mostly in individuals with AIDS-impaired immunity and is thought to be caused by JC polyoma virus (JCV). In MS a neurotrophic virus trigger is suspected, but the precise etiology remains unknown. Human herpesvirus 6 (HHV6) is a ubiquitous, commensal and usually benign beta-herpesvirus. Some researchers have found evidence for HHV6 infection in MS plaques and sera. We recently demonstrated a high frequency of cells containing HHV6 genome in PML lesions, as well as co-infection of oligodendrocytes by JCV and HHV6. This suggests that HHV6 may be a co-factor in the etiology of PML, and raises questions about its role in other demyelinative diseases.


OBJECTIVE
To determine the prevalence and cellular localization of HHV6, JCV and HIV-1 infected cells in PML, MS, AIDS and control CNS tissues, and their potential relationship with disease.


METHODS
An unconventional, sensitive two-step in situ polymerase chain reaction (ISPCR) procedure was used to amplify and detect HHV6, JCV and HIV-1 genomic DNAs in formalin fixed, paraffin-embedded archival CNS tissues. HHV6, JCV and HIV-1 gene expression was detected by ICC for HHV6 p41 and gp101, JCV large T, and HIV-1 p24 gag and NEF proteins.


RESULTS
A high frequency of HHV6 genome was consistently detected in both PML and MS white matter lesional cells; a peri-lesional concentration was notable. HHV6 was found mainly in oligodendrocytes, but neurons were also infected. HHV6 was present in larger amounts than JCV in PML lesions, while more HIV-1 than HHV6 was present in AIDS. Variable amounts of HHV6 genome were detected in normal, AIDS and other control brains; the frequency of infected cells tended to increase with patient age.


CONCLUSIONS
High concentrations of HHV6 genome in association with PML and MS lesions, open the possibility that HHV6 activation may play a role in the pathogenesis of these demyelinative diseases.
Blumberg
B M
BM
VA Bio-Medical Research Institute, Building 7, East Orange VA Medical Center, 385 Tremont Avenue, East Orange, NJ, USA. bbrl@aol.com
Mock
D J
DJ
Powers
J M
JM
Ito
M
M
Assouline
J G
JG
Baker
J V
JV
Chen
B
B
Goodman
A D
AD
D015526:AIDS Dementia Complex / Q000821:virology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000821:virology; D002648:Child; D002675:Child, Preschool; D005260:Female; D015497:HIV-1 / Q000235:genetics / Q000302:isolation & purification; D006566:Herpesviridae Infections / Q000821:virology*; D015654:Herpesvirus 6, Human / Q000235:genetics / Q000302:isolation & purification* / Q000472:pathogenicity*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007223:Infant; D007577:JC Virus / Q000302:isolation & purification; D007968:Leukoencephalopathy, Progressive Multifocal / Q000821:virology*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000821:virology*; D016133:Polymerase Chain Reaction / Q000379:methods*