Detection of JC virus DNA fragments but not proteins in normal brain tissue

Abstract

Objective-Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the white matter affecting immunocompromised patients that results from the cytolytic destruction of glial cells by the human neurotropic JC virus (JCV). According to one model, during the course of immunosuppression, JCV departs from its latent state in the kidney and after entering the brain, productively infects and destroys oligodendrocytes. The goal of this study was to test the hypothesis that JCV may reside in a latent state in a specific region of the brains of immunocompetent (non-PML) individuals without any neurological conditions. Methods-Gene amplification was performed together with immunohistochemistry to examine the presence of JCV DNA sequences and expression of its genome in five distinct regions of the brain from seven immunocompetent non-PML individuals.Results-Although no viral proteins were expressed in any of these cases, fragments of the viral DNA were present in various regions of normal brain. Laser-capture microdissection showed the presence of JCV DNA in oligodendrocytes and astrocytes, but not in neurons.Interpretation-The detection of fragments of viral DNA in non-PML brain suggests that JCV has full access to all regions of the brain in immunocompetent individuals. Thus, should the immune system become impaired, the passing and/or the resident virus may gain the opportunity to express its genome and initiate its lytic cycle in oligodendrocytes. The brain as a site of JCV latency is a possibility.The human polyomavirus, JC virus (JCV), infects greater than 80% of the human population by early adulthood and remains in a persistent state throughout life. 1-3 Under certain pathological conditions, when the immune system is severely impaired, JCV becomes reactivated and its productive replication in oligodendrocytes causes the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). 4,5 Once a rare disease of white matter seen in patients with lymphoproliferative and myeloproliferative disease, 5 PML has been seen more frequently in acquired immune deficiency syndrome patients. 6,7 More recently, it was shown that manipulation of immune cells, both T and B cells, by specific monoclonal antibodies that impair trafficking to the brain may promote JCV replication and the development of PML. 8 The histopathological hallmarks of PML include demyelinated Address correspondence to Dr Khalili, Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, 1900 North 12th Street, 015-96, Room 203, Philadelphia, PA 19122. E-mail: kamel.khalili@temple Similar to its well-studied family member, SV40, the genome of JCV consists of closed, circular, double-stranded DNA of 5130 nucleotides in size 10 with 3 distinct domains: early, late, and control regions (Fig 1). The early region is responsible for expression of a series of proteins, called T antigens, which possess regulatory functions on the viral replication cycle and affect several cellular p...

Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

“…JCV DNA, but generally not protein, has been found in the brains of both healthy and immunocompromised patients without PML or other neurological disorders (31,107,386,485). This suggests that JCV has access to the CNS before disease onset and may travel to, and nonproductively infect, the brains of some immunocompetent individuals.…”

PML-IRIS in patients with HIV infection

“…25 On the other hand, although highly controversial, JCV DNA has also been found in the brain tissues of patients with AIDS without clinically evident PML 35 as well as in normal individuals. 36 Potential mechanisms of PML-IRIS development include an unraveling of a latent subclinical infection triggered by immune recovery or JCV-induced reactivation mediated by cytokines. The concept that treatment of an infectious agent can lead to an augmented immune response with paradoxical deterioration is well recognized in mycobacterium tuberculosis infections.…”

JC Virus Latency in the Brain and Extraneural Organs of Patients with and without Progressive Multifocal Leukoencephalopathy

“…Whether JCV can reach the brain and establish latency in the central nervous systems (CNS) of otherwise-healthy individuals are matters of debate. While some investigators detected JCV DNA in 28 to 68% of frozen (8,27) and 18 to 71% of formalin-fixed, paraffin-embedded (FFPE) (4,7,20) brain samples of patients without PML, others reported negative results (3,6,10,23). Clearly, characterizing JCV sites of latency is imperative in the prevention of viral reactivation and PML.…”