The HHV6 paradox: ubiquitous commensal or insidious pathogen? A two-step in situ PCR approach

• Published in: Journal of clinical virology Vol. 16; no. 3; pp. 159 - 178
• Main Authors: Blumberg, Benjamin M, Mock, David J, Powers, James M, Ito, Masumi, Assouline, Jose G, Baker, Jeffrey V, Chen, Bojun, Goodman, Andrew D
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Amsterdam Elsevier B.V 01.05.2000; Elsevier Science
• Subjects: Adult; Aged; Aged, 80 and over; AIDS Dementia Complex - virology; AIDS/HIV; Biological and medical sciences; Brain - virology; Child; Child, Preschool; CNS demyelinative disease; Female; Herpesviridae Infections - virology; Herpesvirus 6, Human - genetics; Herpesvirus 6, Human - isolation & purification; Herpesvirus 6, Human - pathogenicity; HHV6; HIV-1 - genetics; HIV-1 - isolation & purification; Human herpesvirus 6; Humans; Immunohistochemistry; In Situ Hybridization; Infant; JC virus; JC Virus - isolation & purification; JCV; Leukoencephalopathy, Progressive Multifocal - virology; Male; Medical sciences; Middle Aged; Multiple Sclerosis - virology; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Neurology; Polymerase Chain Reaction - methods; Two-step ISPCR; HHV6; HHV6, human herpesvirus 6; ICC, immunocytochemistry; ISPCR, in situ polymerase chain reaction; MS, multiple sclerosis; CNS, central nervous system; JCV, JC polyoma virus; PML, progressive multifocal leukoencephalopathy; JCV; HIV-1, human immunodeficiency virus; ISH, in situ hybridization; Two-step ISPCR; CNS demyelinative disease; Human; Nervous system diseases; Multiple sclerosis; Prevalence; Herpesviridae; Epidemiology; Cerebral disorder; Inflammatory disease; Progressive multifocal leukoencephalopathy; Infection; Virus; Polymerase chain reaction; Herpesvirus hominis 6; Etiology; Viral disease; Central nervous system disease; Slow virus
• ISSN: 1386-6532; 1873-5967
• DOI: 10.1016/S1386-6532(99)00084-0

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.