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PubMed2003

Unambiguous identification of JC polyomavirus strains transmitted from parents to children.

JC polyomavirus (JCV), the etiological agent of progressive multifocal leukoencephalopathy, is ubiquitous in humans, infecting children asymptomatically, then persisting in renal tissue. It has been proposed that JCV is transmitted mainly from parents to children through long-term cohabitation. The objective of this study was to further elucidate the mode of JCV transmission. In 5 families, we selected parent/child pairs between whom JCV was probably transmitted (judged on the basis of the identity of a 610-bp JCV DNA sequence between the parent and child). We established 5 to 9 complete JCV DNA clones from the urine of each parent or child. The complete sequences of these clones were determined and compared in each family. Nucleotide substitutions were detected in 4 parents and 1 child, and sequence rearrangements (deletions or duplications) were found in 2 parents and 2 children. Phylogenetic comparison of the detected sequences indicated that the diversity of JCV DNA sequences was generated in each family (i.e. not caused by multiple infection). We found that in 4 of the 5 families, a sequence detected in the parent was completely identical to one in the child. These findings provided further support for the proposed mode of JCV transmission, i.e. parent-to-child transmission during cohabitation.

Adult↗

PubMed1997

Five complete genomes of JC virus type 3 from Africans and African Americans.

The central demyelinating disease progressive multifocal leukoencephalopathy (PML) is caused by the human polyomavirus JC virus (JCV). JCV evolved as geographically based genotypes of which Type 3 is an African variant first characterized in HIV-1 positive patients from Tanzania. This study reports the complete sequence of five JCV Type 3 strains. The entire JCV genome was PCR amplified from urine specimens of three African and two African-American individuals. The African consensus sequence was compared to the Type 1 and Type 2 prototype strains, JCV (Mad-1) and JCV(GS/B), respectively. Type 3 differed in 2.2% of its coding region genome from JCV (Mad-1) and in 1.3% from JCV(GS/B). Within the coding region the sequence variation among the three types was higher in the capsid protein VP1 and in the regulatory protein large T antigen than in the agnoprotein or in VP2/3. Notable Type 3-specific changes were located at sites adjacent to the zinc finger motif and near the major donor and acceptor splice junctions of large T antigen. Four of the five urinary Type 3 strains had an unrearranged, archetypal regulatory region. African strain #309 showed a 10-bp deletion at a location similar to that previously described for #307 from Tanzania. The African-American Type 3 strain #312 was closely related to the African consensus sequence. The complete genome of a urinary JCV strain from another African-American male, previously reported as a possible Type 5, showed a sequence difference of only 0.52% from the Tanzanian consensus and has been reclassified as a subtype of Type 3.

Amino Acid Sequence↗

PubMed2001

New JC virus (JCV) genotypes from papua new guinea and micronesia (type 8 and type 2E) and evolutionary analysis of 32 complete JCV genomes.

The JC virus (JCV) is a ubiquitous human polyomavirus that frequently resides in the kidneys of healthy individuals and is excreted in the urine of a large percentage of the population. Geographic-specific JCV variants, isolated from urine and from brain of progressive multifocal leukoencephalopathy (PML) patients, have been grouped into seven distinct genotypes based on whole genome analysis and by individual polymorphic nucleotides (typing sites) in the VP1 coding region. Mutations in the archetypal regulatory region, sometimes consisting of deletions and/or duplications, are also useful taxonomic characters for further characterizing and subdividing genotypes. Investigation of JCV variation in Papua New Guinea (PNG) revealed three distinct variants called PNG- 1, PNG-2, and PNG-3. These variants exhibited consistent coding region and regulatory region mutations. Evolutionary analysis of 32 complete JCV genomes including six new viral genomes from the western Pacific suggests that the new PNG JCV variants are closely associated with the broad group of Type 2 strains of JCV found throughout Asia, forming a monophyletic group with the Northeast Asian strains (Type 2A). Within the Type 2 clade, however, the PNG JCV variants cluster as two distinct groups and are therefore described here as new JCV genotypes designated Type 2E and Type 8.

Adult↗

PubMed2001

Differential diagnosis of posterior fossa multiple sclerosis lesions--neuroradiological aspects.

Various infratentorial pathological conditions can mimic multiple sclerosis (MS) both clinically and radiologically. We review the inflammatory, vascular, neoplastic and metabolic conditions which show features similar to those of MS on magnetic resonance imaging (MRI). Behcet's disease, Lyme disease, progressive multifocal leukoencephalopathy, neurosarcoidosis, Whipple's disease, listeria rhombencephalitis, Bickerstaff's brainstem encephalitis, vasculitis due to systemic lupus erythematosus, and acute disseminated encephalomyelitis produce inflammatory lesions similar to those of MS in the brainstem and cerebellum. Neoplastic diseases, in particular pontine gliomas and lymphomas, can mimic MS. Vascular ischaemic lesions, either due to infarction produced by occlusion of a major posterior circulation artery or due to small vessel vasculopathy, can lead to posterior fossa lesions. The MRI changes of central pontine myelinolysis can also mimic MS. Diffuse axonal injury, radiation and chemotherapy induce lesions that resemble MS, however the clinical history will exclude these possibilities. Finally, we discuss a few conditions which are similar to MS in clinical presentation but have different MRI appearances, such as brainstem cavernomas, posterior fossa tumoural lesions, aneurysms and vascular loops producing neurovascular conflicts. Analysis of the MRI findings with clinical history and laboratory data helps to narrow down the diagnosis of the infratentorial pathology.

Brain↗

PubMed2004

Adenosine deaminase activity in cerebrospinal fluid of HIV-infected patients: limited value for diagnosis of tuberculous meningitis.

Adenosine deaminase activity (ADA) determination in cerebrospinal fluid (CSF) is considered a specific test for the diagnosis of tuberculous meningitis. In order to study the variability of this marker in patients with different neurological disorders associated with HIV infection, and its utility for the diagnosis of tuberculous meningitis in these patients, the ADA levels in 417 CSF samples from HIV-infected patients with neurological symptoms were reviewed. HIV infection, HIV-associated neurological disorders, and progressive multifocal leukoencephalopathy were not associated with elevated ADA in CSF. Among patients with meningitis, receiver operating characteristic curve analysis gave an optimal ADA cut-off point of 8.5 IU/l for the diagnosis of tuberculous meningitis, with 57% sensitivity, 87% specificity, and an area under the curve of 0.747 (similar to that for CSF glucose concentration). False-positive results were found in patients with neurological CMV disease and cryptococcal, lymphomatous, and probable candidal meningitis. The results of this study indicate that ADA determination in CSF has limited utility for the diagnosis of tuberculous meningitis in HIV-infected patients.

AIDS-Related Opportunistic Infections↗

PubMed2006

The role of sialic acid in human polyomavirus infections.

JC virus (JCV) and BK virus (BKV) are human polyomaviruses that infect approximately 85% of the population worldwide [1,2]. JCV is the underlying cause of the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML), a condition resulting from JCV induced lytic destruction of myelin producing oligodendrocytes in the brain [3]. BKV infection of kidneys in renal transplant recipients results in a gradual loss of graft function known as polyomavirus associated nephropathy (PVN) [4]. Following the identification of these viruses as the etiological agents of disease, there has been greater interest in understanding the basic biology of these human pathogens [5,6]. Recent advances in the field have shown that viral entry of both JCV and BKV is dependent on the ability to interact with sialic acid. This review focuses on what is known about the human polyomaviruses and the role that sialic acid plays in determining viral tropism.

Humans↗

PubMed2003

BKV-DNA and JCV-DNA in CSF of patients with suspected meningitis or encephalitis.

BACKGROUND: Few studies have looked for the polyoma viruses JC or BK virus in the central nervous system (CNS) of patients without neurological symptoms or with neurological symptoms other than progressive multifocal leukoencephalopathy (PML). PCR-microplate hybridization method was employed for the detection of BKV-DNA or JCV-DNA in cerebrospinal fluid (CSF) specimens from patients with suspected meningitis or encephalitis. MATERIALS AND METHODS: A total of 181 CSF specimens from 151 patients with suspected meningitis or encephalitis was examined for BKV or JCV using PCR-microplate hybridization method. None of the patients had (clinically diagnosed) PML. A control group consisting of 20 CSF specimens from normal subject was also included. RESULTS: BKV DNA was found in five out of 131 (3.8%) and JCV DNA in two out of 131 (1.5%) of the patients with suspected meningitis or encephalitis by PCR ELISA. BKV or JCV DNA was not detected in CSF samples of any of 19 HIV positive patients. BKV and JCV DNAs were detected respectively in two CSF samples in which Mycobacterium tuberculosis (TB) PCR was also positive. Another patient who was positive for JCV PCR died with a diagnosis of cerebral lymphoma. Among the BK virus infected patients there was a patient with a previous history of hemolytic uremia and acute renal failure. Neither BKV nor JCV DNA was found in any of the 20 CSF samples from normal patients undergoing lumbar puncture for myelography as a part of an investigation of lower back pain. CONCLUSION: These results suggest that BK virus may be associated with neurological diseases either in immunocompetent or immunocompromised patients. Detection of BKV and JCV DNA in the CSF of the patients suspected to have either meningitis or encephalitis suggests that these viruses may have an etiological role. Thus, diagnostic tests for BK and JC viruses should be included in the investigative program for meningitis or encephalitis patients.

Adult↗

PubMed1994

A pathologically distinct new form of HIV associated encephalopathy.

We present the clinical, morphological and neuropathological findings in a 44-year-old male suffering from the acquired immunodeficiency syndrome (AIDS) (CDC stage IV C2) who presented with rapidly progressive right-side hemiparesis and developed hemianopia and aphasia. Scans showed multiple, not contrast-enhancing, not space-occupying echo-intensive lesions in T2-weighted MR-imaging. No hint for an opportunistic infection, necrotizing vasculitis or vascular disease was found. All therapeutic regimens failed and 8 weeks after onset of neurological symptoms the patient died because of cardiorespiratory arrest. Post-mortem examination excluded opportunistic infection, progressive multifocal leukoencephalopathy, lymphoma, vasculitis and ischemia of the brain. In the presence of an unusually high amount of HIV-infected macrophages at immunohistochemical examination, the overall pathological findings were atypical both for HIV encephalitis and HIV leukoencephalopathy. We describe a pathologically distinct new form of HIV associated encephalopathy.

AIDS Dementia Complex↗

PubMed1992

Persistence of archetypal JC virus DNA in normal renal tissue derived from tumor-bearing patients.

JC virus DNAs derived from the urine of nonimmunosuppressed individuals generally contain an archetypal regulatory region which may have generated various regulatory regions of JC virus from from the brain with progressive multifocal leukoencephalopathy (PML). In this study, we examined whether JC virus persisting in normal human kidney tissue contains the archetypal regulatory region. Renal medulla, cortex, and tumor from 32 patients bearing renal tumors were screened for JC virus DNA by blot hybridization. Viral DNA was detected in the medulla in 13 cases (41%), in the cortex in 2 cases (6%), but not at all from the tumor. A number of viral DNA-positive specimens (8 from the medulla and 2 from the cortex) were used to amplify and sequence viral regulatory regions by polymerase chain reaction. Structures of the regulatory regions from all the specimens were, with a few nucleotide variations, identical with that of the archetypal region which was previously detected in the JC virus DNA from urine. This finding supports the hypothesis that the JC virus associated with PML evolved from the archetypal JC virus during persistence in human hosts. Furthermore, we present evidence that renal JCV is replicating and that progeny virions are excreted into the urine.

Adult↗

PubMed1992

Evidence of human polyomavirus BK and JC infection in normal brain tissue.

Infection with the polyomaviruses JC and BK is ubiquitous in the human population and JCV is the only virus associated with the central nervous system disease progressive multifocal leukoencephalopathy. In the attempt to analyze the pathogenesis of polyomavirus infections we asked whether human polyomaviruses invade the brain during persistence. Brain autopsy material from 67 individuals with disorders other than PML was examined for the presence of polyomavirus DNA. Southern blot analysis demonstrated JCV-specific full-length virus genomes in healthy brain tissue in about 20% of the patients. Type-specific analysis with polymerase chain reaction and sequencing confirmed these data. Additionally, the presence of BKV DNA sequences covering an early gene fragment and the control region with flanking early and late protein coding sequences was detected. Cloning of the complete BKV genome from two cases supported the assumption that not only full-length JCV DNA was present in those tissue specimens but also BKV genomes. The data obtained demonstrate that dual infection of the brain with the polyomaviruses JCV and BKV is a common event and give strong evidence that both viruses frequently establish a latent CNS infection.

BK Virus↗

PubMed1992

Interaction of the human polyomavirus, JCV, with human B-lymphocytes.

The human polyomavirus, JCV, is the causative agent of the central nervous system demyelinating disease progressive multifocal leukoencephalopathy (PML). The principal target of JCV infection in the central nervous system (CNS) is the myelinating oligodendrocyte. However, the site of JCV multiplication outside of the CNS and the mechanism by which virus gains access to the brain are not known. Recently, JCV infected B-lymphocytes have been demonstrated in PML patients in several lymphoid organs, in circulating peripheral lymphocytes, and in brain, suggesting a possible role of B-lymphocytes in the dissemination of virus to the brain. The experiments reported here were undertaken to understand more about the interactions of JCV with human B-lymphocytes. The data show that JCV is able to multiply in either Epstein-Barr virus transformed (EBV) or EBV negative human B cell lines resulting in production of infectious, progeny virions. In addition, nuclear proteins extracted from these B cells bind to similar nucleotides within the JCV regulatory region that are bound by nuclear proteins extracted from human fetal glial cells, the most susceptible host and principal target cell for JCV infection in vitro. It is not known, however, whether these DNA binding proteins from susceptible B cells and glial cells are similar.

B-Lymphocytes↗

PubMed1992

Neuropathology of the spinal cord in the acquired immunodeficiency syndrome.

The neuropathologic findings in the spinal cord were reviewed in 138 consecutive autopsies of patients with the acquired immunodeficiency syndrome. In all cases both the brain and spinal cord were examined by conventional histologic techniques, and in 63 cases immunohistochemistry was used to detect human immunodeficiency virus (HIV), Toxoplasma gondii, cytomegalovirus, and JC papovavirus antigens. The most common observation was a normal spinal cord (60%). Vacuolar myelopathy (VM) was observed in 23 (17%) cases. Human immunodeficiency virus myelitis was evident in 8% of cases. Human immunodeficiency virus myelitis was associated with HIV encephalitis in 65% of the cases. Opportunistic infections of the spinal cord were uncommon, consisting of cryptococcosis (five cases), cytomegalovirus (four cases), toxoplasmosis (one case), and progressive multifocal leukoencephalopathy (one case), and almost always were seen with cerebral and/or systemic infection by these agents. Malignant lymphoma rarely involved the spinal cord (four cases); all were B-cell lymphomas and were associated with cerebral and/or systemic lymphoma. Other abnormalities rarely observed were Wallerian degeneration of the corticospinal tracts or posterior columns (6%) and focal microinfarcts. Most cases of VM (78%) were not associated with HIV myelitis, and in the five patients with both VM and HIV myelitis, HIV-infected cells were not found in the regions affected by VM. In contrast, 65% of cases with VM were associated with HIV encephalitis. The pathogenesis of VM remains unknown; it is probably not due to direct infection by HIV.

Acquired Immunodeficiency Syndrome↗

PubMed1986

The early region of human papovavirus JC induces dysmyelination in transgenic mice.

Transgenic mice containing the early region of human papovavirus JC were produced. Some of these mice exhibited a shaking disorder similar to the previously described mutant mice jimpy or quaking. Neuropathological analysis indicated a dysmyelination in the central nervous system, but not the peripheral nervous system. A high level of JCV T-antigen mRNA was present in the brains of the mice exhibiting the myelin disorder. JC virus is associated in humans with a degenerative demyelinating disease: progressive multifocal leukoencephalopathy. The JCV-containing transgenic mice may therefore provide an animal model for studying this disease.

Animals↗

PubMed1988

Encephalomyelitis and demyelinating diseases in patients with extracerebral malignant tumors.

We examined central nervous system (CNS) lesions in 456 patients with primary extracerebral malignant tumors. Inflammatory reactions caused by viral (progressive multifocal leukoencephalopathy (PML), herpes zoster varicella), fungal, or bacterial infections could be demonstrated in 20 patients. In a further 19 patients, the brain tissue showed lymphocyte infiltrates of unknown etiology and, in four of these, autopsy revealed probable paraneoplastic, non-bacterial, endocarditis as a possible explanation for the local inflammatory reaction. The frequency of thrombophlebitis, non-arteriosclerotic thrombosis and arteritis was significantly higher than in a control group of 2052 tumor-free patients. Focal spongiform-axonopathic lesions (24 cases) as well as diffuse leukoencephalopathy (11 cases) were interpreted as probably being at least in part paraneoplastic because the same alterations could also be observed in patients who had never undergone cytostatic or radiation therapy. The possible pathogenetic conditions are discussed and a classification of these tumor-accompanying, but not always tumor-dependent, lesions suggested.

Brain↗

PubMed1992

Morphology of demyelination in the human central nervous system.

The principles of the neuropathological classification of disorders of central nervous system myelin are recalled. They are illustrated by a few selected examples. Dysmyelination is characterized by the production of an abnormal and unstable myelin sheath; it is often associated with hypomyelination (paucity of myelin formation) and is due to metabolic disorders. It is the main process in leukodystrophies. Storage of different lipids (e.g. sulfatides, long-chain fatty acids) or associated pathology of various cell types (in Alexander's disease, for example) are used for classifying these disorders. Biochemical and genetic characterizations are presently ongoing. Demyelination is the destruction of apparently normal myelin. It is often followed by remyelination. Our present knowledge on the neuropathology of multiple sclerosis, the most common demyelinating disease, is summarized. Cell-mediated demyelination affects the myelin sheaths for an obscure reason. The causes of the multifocal and sharply demarcated plaques, and of the fading of the remyelination process at the edge of some plaques, are not clear. A few examples of demyelinating diseases of known etiology and of various mechanisms are given. The similarities between acute disseminated leukoencephalitis and experimental autoimmune encephalitis are stressed. In progressive multifocal leukoencephalopathy, chronic infection of oligodendrocytes by JC virus induces poorly defined areas of demyelination. In AIDS, the pathogenesis of the myelin change is unclear. Macrophages may be responsible. Toxic and vascular disorders provide also good models for the understanding of mechanisms of demyelination.

Central Nervous System Diseases↗

PubMed1987

Genetic characterization of JC virus Tokyo-1 strain, a variant oncogenic in rodents.

The genome DNA of JC virus Tokyo-1 strain [JCV(Tokyo-1)], a variant oncogenic in rodents, was molecularly cloned directly from the brain of a Japanese patient with progressive multifocal leukoencephalopathy and from tissue culture, and the restriction enzyme cleavage pattern and regulatory sequences were determined. The restriction pattern of the cloned JCV(Tokyo-1) DNA was different from those of JCVs previously reported in the United States and Germany. Also, the arrangement of the regulatory sequence was unique to this strain. Thus JCV(Tokyo-1) can be classified as a new subtype. The relationship between the restriction pattern and the regulatory sequence of JCV(Tokyo-1), and its characteristic oncogenicity, is discussed.

Animals↗

PubMed1991

Comparison of regulatory sequences and enhancer activities of SV40 variants isolated from patients with neurological diseases.

The genomic regulatory regions of human isolates of SV40 were compared by nucleotide sequencing and by biological assays of their transcriptional enhancers. SVAST is a defective genome and SVMEN an infectious genome molecularly cloned from human astrocytoma and meningioma, respectively (Krieg and Scherer, 1984). SVPML is an isolate from a case of progressive multifocal leukoencephalopathy (Weiner et al., 1972). SVAST contains a duplication of the regulatory region. One copy is virtually identical to that of SV40; the other bears a deletion of the minimal enhancer and is associated with an insertion of early/late sequences derived from the terminus of replication. The latter copy, together with its insertion, is inserted at nucleotide 4966 (SV40 number). SVMEN has an almost exact deletion of one of the 72-base-pair repeats of the natural SV40 enhancer. The regulatory sequences of SVPML were reported earlier (Martin, 1989). The enhancer activity in CV-1 cells of the lytic virus, SVPML, is 36% that of SV40. In contrast, the SVAST and SVMEN enhancers are more effective, being equal to or 64% that of SV40, respectively. The possibility that SVPML and SVAST/SVMEN originated from different variants of SV40 is discussed.

DNA, Viral↗

PubMed1994

Nested PCR for detection of BK virus and JC virus DNA.

BACKGROUND: A nested polymerase chain reaction (PCR) was developed to detect BK virus (BKV) and JC virus (JCV) DNA sequences. The unique clevage site for BamHI restriction enzyme was located in the JCV amplimer and cleavage was used to differentiate between BKV and JCV. STUDY DESIGN: Twenty-three urine specimens from 17 bone marrow recipients with haemorrhagic cystitis and one liver transplant patient were tested for the presence of BKV and JCV DNA. Four brain tissue specimens (paraffin embedded brain tissues and a fresh frozen brain biopsy) and 5 cerebrospinal fluids from 3 AIDS patients and one liver transplant patient, all with progressive multifocal leukoencephalopathy (PML), were also examined by PCR. RESULTS: The sensitivity of the PCR was 10 genomes for each virus. BKV DNA was detected in 15 urine specimens from 12 bone marrow transplant patients. JCV DNA was detected in 4 cerebrospinal fluids and 4 brain tissues from patients with PML. CONCLUSION: Our results show that the nested PCR is a sensitive and rapid assay that can be used for diagnosis of BKV and JCV infections. The cerebrospinal fluid appears to be a suitable material for diagnosis of JC virus reactivation in the brain.

Journal Article↗