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The HHV6 paradox: ubiquitous commensal or insidious pathogen? A two-step in situ PCR approach
B M Blumberg1, D J Mock, J M Powers
1VA Bio-Medical Research Institute, Building 7, East Orange VA Medical Center, 385 Tremont Avenue, East Orange, NJ, USA. bbrl@aol.com
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.
Objectives:
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.
Study Design:
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.
Insights
Human herpesvirus 6 (HHV6) DNA was found in high concentrations in progressive multifocal leukoencephalopathy (PML) and multiple sclerosis (MS) lesions. This suggests HHV6 may contribute to the development of these demyelinating diseases.
Area of Science:
- Neurovirology
- Immunology
- Pathology
Background:
- Progressive multifocal leukoencephalopathy (PML) and multiple sclerosis (MS) are central nervous system (CNS) demyelinating diseases with distinct etiologies.
- JC polyoma virus (JCV) is implicated in PML, while the cause of MS remains unknown.
- Human herpesvirus 6 (HHV6) is a common virus, and its potential role in demyelinating diseases is under investigation.
Purpose of the Study:
- To investigate the prevalence and location of HHV6, JCV, and HIV-1 infected cells in CNS tissues from PML, MS, AIDS, and control groups.
- To explore the potential association between these viral infections and the pathogenesis of demyelinating diseases.
Main Methods:
- Utilized a sensitive two-step in situ polymerase chain reaction (ISPCR) to detect viral genomic DNA in archival CNS tissues.
- Employed immunohistochemistry (ICC) to detect viral protein expression for HHV6, JCV, and HIV-1.
Main Results:
- High frequencies of HHV6 genome were detected in white matter lesions of both PML and MS patients, particularly in oligodendrocytes.
- HHV6 was more abundant than JCV in PML lesions, and HIV-1 was more prevalent than HHV6 in AIDS cases.
- HHV6 DNA was also found in control brains, with increased frequency correlating with patient age.
Conclusions:
- The significant presence of HHV6 in PML and MS lesions suggests its potential role as a co-factor in the pathogenesis of these demyelinating diseases.
- Further research is warranted to elucidate the precise mechanisms by which HHV6 may contribute to CNS demyelination.