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PubMed1997

Asian genotypes of JC virus in Native Americans and in a Pacific Island population: markers of viral evolution and human migration.

The human polyomavirus JC (JCV) causes the central nervous system demyelinating disease progressive multifocal leukoencephalopathy. Previously, we showed that 40% of Caucasians in the United States excrete JCV in the urine as detected by PCR. We have now studied 68 Navaho from New Mexico, 25 Flathead from Montana, and 29 Chamorro from Guam. By using PCR amplification of a fragment of the VP1 gene, JCV DNA was detected in the urine of 45 (66%) Navaho, 14 (56%) Flathead, and 20 (69%) Chamorro. Genotyping of viral DNAs in these cohorts by cycle sequencing showed predominantly type 2 (Asian), rather than type 1 (European). Type 1 is the major type in the United States and Hungary. Type 2 can be further subdivided into 2A, 2B, and 2C. Type 2A is found in China and Japan. Type 2B is a subtype related to the East Asian type, and is now found in Europe and the United States. The large majority (56-89%) of strains excreted by Native Americans and Pacific Islanders were the type 2A subtype, consistent with the origin of these strains in Asia. These findings indicate that JCV infection of Native Americans predates contact with Europeans, and likely predates migration of Amerind ancestors across the Bering land bridge around 12,000-30,000 years ago. If JCV had already differentiated into stable modern genotypes and subtypes prior to first settlement, the origin of JCV in humans may date from 50,000 to 100,000 years ago or more. We conclude that JCV may have coevolved with the human species, and that it provides a convenient marker for human migrations in both prehistoric and modern times.

Biomarkers↗

PubMed1995

Cell-specific activation of the glial-specific JC virus early promoter by large T antigen.

JC virus causes the human demyelinating disease progressive multifocal leukoencephalopathy by selective infection of glial cells. This cell specificity results from glial-specific expression of viral early genes (large and small T antigens). Analysis of transcriptional regulation by the MH1 JC virus early promoter demonstrates that glial specificity is directed by the basal promoter. Because T antigen regulates the basal region of several viral and cellular promoters, we investigated whether it controls the JC virus basal promoter in a glial-specific manner. A JC virus T antigen expression plasmid generated a 95-kDa protein which exhibited nuclear localization and physical association with p53. T antigen repressed the JC virus and SV40 early promoters 4- to 5-fold in glioma cells. Conversely, T antigen induced 100- to 200-fold activation of the JC virus early promoter in nonglial cells, whereas the SV40 promoter was repressed. Activation required the JC virus TATA box sequence and a pentanucleotide repeat immediately upstream of the TATA box, but was independent of the upstream enhancer region. These data demonstrate that the JC virus basal promoter is responsible for glial-specific gene expression and suggest a mechanism for this regulation.

Antigens, Polyomavirus Transforming↗

PubMed2000

Transcriptional activation of JC virus by human T-lymphotropic virus type I Tax protein in human neuronal cell lines.

Polyomavirus JC (JCV) causes the human demyelinating disease, progressive multifocal leukoencephalopathy (PML). The recent demonstration of cases of PML in association with human T-lymphotropic virus type I (HTLV-I) infection prompted us to examine whether the HTLV-I-encoded regulatory protein Tax activates JCV transcription. By employing a dual luciferase assay, we initially found that the expression of Tax activated the transcriptional potential of both early and late promoters of JCV in human neuronal but not in non-neuronal cells. We subsequently analyzed the mechanism of Tax-induced activation of the JCV promoter in neuronal cells with the following results: 1) the JCV promoter that lacks the NF-kappaB-binding motif could not be activated by Tax; 2) the overexpression of IkappaBalpha abolished Tax-induced transcriptional activation of the JCV promoter; 3) a Tax mutant (M22) lacking the potential for activation via the NF-kappaB pathway did not activate the JCV promoter. Furthermore, Tax enhances the gene expression of JCV T antigen and VP1. We examined mechanisms of the cell-specific activation of the JCV promoter by Tax. Electrophoretic mobility shift assay demonstrated the presence of Tax-bound protein(s) that were specifically present in non-neuronal cells. This study is the first demonstration of the activation of JCV promoter by HTLV-I Tax in an NF-kappaB-dependent manner.

Base Sequence↗

PubMed2004

Nuclear entry mechanism of the human polyomavirus JC virus-like particle: role of importins and the nuclear pore complex.

JC virus (JCV) belongs to the polyomavirus family of double-stranded DNA viruses and causes progressive multifocal leukoencephalopathy in humans. Although transport of virions to the nucleus is an important step in JCV infection, the mechanism of this process has remained unclear. The outer shell of the JCV virion comprises the major capsid protein VP1, which possesses a putative nuclear localization signal (NLS), and virus-like particles (VLPs) consisting of recombinant VP1 exhibit a virion-like structure and physiological functions (cellular attachment and intracytoplasmic trafficking) similar to those of JCV virions. We have now investigated the mechanism of nuclear transport of JCV with the use of VLPs. Wild-type VLPs (wtVLPs) entered the nucleus of most HeLa or SVG cells. The virion structure of VLPs was preserved during transport to the nucleus as revealed by confocal microscopy of cells inoculated with fluorescein isothiocyanate-labeled wtVLPs containing packaged Cy3. The nuclear transport of wtVLPs in digitonin-permeabilized cells was dependent on the addition of importins alpha and beta and was prevented by wheat germ agglutinin or by antibodies to the nuclear pore complex. The nuclear entry of VLPs composed of VP1 with a mutated NLS was greatly inhibited, compared with that of wtVLPs, in both intact and permeabilized cells. Unlike wtVLPs, the mutant VLPs did not bind to importins alpha or beta. Limited proteolysis analysis revealed that the NLS of VP1 was exposed on the surface of wtVLPs. These results suggest that JCV VLPs bind to cellular importins via the NLS of VP1 and are transported into the nucleus through the nuclear pore complex.

Amino Acid Sequence↗

PubMed2005

Identification of FEZ1 as a protein that interacts with JC virus agnoprotein and microtubules: role of agnoprotein-induced dissociation of FEZ1 from microtubules in viral propagation.

The human polyomavirus JC virus (JCV) is the causative agent of a fatal demyelinating disease, progressive multifocal leukoencephalopathy, and encodes six major proteins, including agnoprotein. Agnoprotein colocalizes with microtubules in JCV-infected cells, but its function is not fully understood. We have now identified fasciculation and elongation protein zeta 1 (FEZ1) as a protein that interacted with JCV agnoprotein in a yeast two-hybrid screen of a human brain cDNA library. An in vitro binding assay showed that agnoprotein interacted directly with FEZ1 and microtubules. A microtubule cosedimentation assay revealed that FEZ1 also associates with microtubules and that agnoprotein induces the dissociation of FEZ1 from microtubules. Agnoprotein inhibited the promotion by FEZ1 of neurite outgrowth in PC12 cells. Conversely, overexpression of FEZ1 suppressed JCV protein expression and intracellular trafficking in JCV-infected cells. These results suggest that FEZ1 promotes neurite extension through its interaction with microtubules, and that agnoprotein facilitates JCV propagation by inducing the dissociation of FEZ1 from microtubules.

Adaptor Proteins, Signal Transducing↗

PubMedDate not supplied

Oral hairy leukoplakia: an ultrastructural study and review of the literature.

A 39-year-old, homosexual, Caucasian man with a 9-month history of acquired immunodeficiency syndrome by reduced CD4 lymphocyte count alone was found to have extensive, asymptomatic, nonremovable, corrugated, white patches on the lateral borders and ventral aspects of the tongue typical of oral hairy leukoplakia (OHL). Histologically, irregular hyperparakeratosis, acanthosis, and clusters of ballooned keratinocytes in the stratum spinosum were present in the biopsied lateral tongue. Some of the superficial ballooned keratinocytes had peripherally beaded nuclei, whereas others had ground glass intranuclear inclusions. Ultrastructurally, the ballooned keratinocytes had three important findings of diagnostic significance. First, frequent herpesvirus nucleocapsids were largely confined to superficial ballooned keratinocytes having marginated and condensed chromatin. In searching for herpesvirus nucleocapsids, the marginated and condensed chromatin was an invaluable marker for cells harboring the virions. Second, the marginated and condensed chromatin frequently had a distinctive punched-out or cribriform appearance. Third, the ground glass intranuclear inclusion bodies consisted of central, medium electron-dense, finely granular material containing frequent herpesvirus nucleocapsids and partially surrounded or capped by prominent, clumped chromatin. The patient died with progressive multifocal leukoencephalopathy 24 months after OHL was diagnosed.

Acquired Immunodeficiency Syndrome↗

PubMed2002

Proceedings of the 10th International Conference on Neuroscience of HIV Infection: emerging issues.

The 10th International Conference on Neuroscience of HIV Infection was held conjointly with the 4th International Symposium on NeuroVirology. This review summarizes a number of important topics addressed at the conference including clinical aspects of HIV-1 associated dementia and peripheral nervous system pathology and their epidemiology in the era of highly active antiretroviral therapy. The neuropathogenesis was discussed with a special focus on different cellular compartments involved, viral and non-viral factors, immune activation, and alterations of the blood-brain barrier, animal models and their relevance for understanding HIV dementia. New aspects of antiretroviral therapy as well as immunization were covered. Neuroradiological approaches including new MR techniques and neuropsychological tests were presented. Viral opportunistic infections (e.g., JCV infection resulting in progressive multifocal leukoencephalopathy) as well as coinfection with hepatitis C represented a further topic.

AIDS Dementia Complex↗

PubMed2002

The epidemiology of human immunodeficiency virus-associated neurological disease in the era of highly active antiretroviral therapy.

Highly active antiretroviral therapy (HAART) is effective in suppressing systemic human immunodeficiency virus (HIV) viral load and has decreased mortality rates and the incidence of systemic opportunistic infections in patients with acquired immunodeficiency syndrome (AIDS). Multiple studies now suggest that the incidence rates of HIV-associated neurological disease and central nervous system (CNS) opportunistic infections also are decreasing. Since the introduction of HAART in 1996, the incidence of HIV dementia has decreased by approximately 50%. The mean CD4 cell count for new cases of HIV dementia is increasing, but it remains as a complication of moderate-advanced immunosuppression. The incidence of HIV-associated distal sensory polyneuropathy has decreased, although the incidence of antiretroviral drug-induced toxic neuropathy has increased. However, as patients with AIDS live longer as a result of HAART, the prevalence of peripheral neuropathy in HIV-seropositive patients may be increasing. The incidence rates of CNS opportunistic infections (cryptococcal meningitis, toxoplasmosis, progressive multifocal leukoencephalopathy) and primary CNS lymphoma have decreased since the introduction of HAART. As patients develop increasing resistance mutations to antiretroviral drugs and with subsequent decline in CD4 cell counts, in the near future, the incidence of HIV-associated neurological disease may begin to rise.

AIDS Dementia Complex↗

PubMed2002

Molecular studies of cerebrospinal fluid in human immunodeficiency virus type 1-associated opportunistic central nervous system diseases--an update.

Although the incidence of opportunistic central nervous system (CNS) diseases has markedly declined in developed countries following the advent of highly active antiretroviral therapies (HAARTs), they still represent a major diagnostic and therapeutic challenge over the world. The application of nucleic acid amplification techniques to the study of cerebrospinal fluid (CSF) has contributed substantially to their diagnosis. The detection of specific microbial genomes in the CSF is now the preferred test for some CNS opportunistic diseases, such as progressive multifocal leukoencephalopathy or cytomegalovirus encephalitis. More recent developments of these techniques are the quantitative amplification techniques and postamplification studies. Quantification of nucleic acids in CSF is an important aid both at the time of diagnosis, for the interpretation of positive findings, and during patient follow-up. Postamplification analyses can provide important information with regard to clinical patient management, e.g., detection of genotypic resistance to antimicrobial drugs, and in the attempt to elucidate disease epidemiology and pathogenesis.

AIDS Dementia Complex↗

PubMed2003

Virus demyelination.

A number of viruses can initiate central nervous system (CNS) diseases that include demyelination as a major feature of neuropathology. In humans, the most prominent demyelinating diseases are progressive multifocal leukoencephalopathy, caused by JC papovirus destruction of oligodendrocytes, and subacute sclerosing panencephalitis, an invariably fatal childhood disease caused by persistent measles virus. The most common neurological disease of young adults in the developed world, multiple sclerosis, is also characterized by lesions of inflammatory demyelination; however, the etiology of this disease remains an enigma. A viral etiology is possible, because most demyelinating diseases of known etiology in both man and animals are viral. Understanding of the pathogenesis of virus-induced demyelination derives for the most part from the study of animal models. Studies with neurotropic strains of mouse hepatitis virus, Theiler's virus, and Semliki Forest virus have been at the forefront of this research. These models demonstrate how viruses enter the brain, spread, persist, and interact with immune responses. Common features are an ability to infect and persist in glial cells, generation of predominantly CD8(+) responses, which control and clear the early phase of virus replication but which fail to eradicate the infection, and lesions of inflammatory demyelination. In most cases demyelination is to a limited extent the result of direct virus destruction of oligodendrocytes, but for the most part is the consequence of immune and inflammatory responses. These models illustrate the roles of age and genetic susceptibility and establish the concept that persistent CNS infection can lead to the generation of CNS autoimmune responses.

Animals↗

PubMed2003

Brain tumors and polyomaviruses.

Polyomaviruses, including JC virus (JCV), BK virus (BKV), and simian virus 40 (SV40) have attracted much attention in the past decade due to their repeated isolation from various human tumors, including those originating from the central nervous system (CNS). JCV and BKV are considered to be ubiquitous human pathogens that become reactivated under impaired physiological conditions such as immunosuppression. Productive replication of JCV and BKV induces diseases such as progressive multifocal leukoencephalopathy in the brain and hemorrhagic or nonhemorrhagic cystitis and nephritis in the kidney. JCV DNA sequences have been isolated from a number of human CNS tumors, including medulloblastoma, ependymoma, and a broad range of glial-origin neoplasms. SV40, once believed to be a monkey virus, has now been isolated from a variety of human cancer cells, including mesothelioma, ependymoma, and non-Hodgkin's lymphoma. In this mini-review, the authors focused their attention on the possible involvement of polyomaviruses, such as JCV, BKV, and SV40, with human brain tumors.

Animals↗

PubMed2003

Molecular analysis of JC virus genotypes circulating among the Italian healthy population.

JC virus (JCV) is an unique virus, but eight different JCV genotypes and various subtypes have been individuated, with a geographic distribution that has been described in general but still needs to be detailed. To define JCV genotype epidemiology in Italy, the authors collected urine from 211 healthy individuals living in Northern, Central, and Southern Continental Italy, and in the two main Italian islands. As screening, JCV DNA was searched using a polymerase chain reaction (PCR) designed to amplify the highly conserved large T (LT) antigen-coding region. Then, to define JCV genotype and trascriptional control region (TCR) organization, fragments of major capsid protein (VP1) and TCR region were amplified and subjected to nucleotide sequencing. The mean frequency of JCV viruria was of 46%, without differences among the four geographically divided groups and between females and males. JCV types 1 and 4 were the most frequently detected, whereas JCV type 2 was rare, and type 3 was found only in one subject. The low frequency of JCV type 2 contrasts with the reported high frequency of this subtype in progressive multifocal leukoencephalopathy (PML), and supports its specific role in PML. The data indicate that JCV genotype epidemiology in Italy is quite different from that of other European countries; moreover, differences between the various Italian regions have been observed. An unexpected high frequency of a new variant of JCV type 4 with a stable point mutation (C --> G) at nucleotide 1851 was found. Furthermore, all the urinary strains had a TCR showing an archetypal organization.

Adult↗

PubMed2004

Detection of the archetypal regulatory region of JC virus from the tonsil tissue of patients with tonsillitis and tonsilar hypertrophy.

The regulatory regions of JC virus (JCV) DNAs in the brain of patients with progressive multifocal leukoencephalopathy (PML) (designated as PML-type regulatory regions) are hypervariable, whereas those in the urine and renal tissue of individuals without PML have the same basic structure, designated as the archetype. It is thought that JCV strains with the archetypal regulatory region circulate in the human population. Nevertheless, Monaco et al (J Virol 70: 7004-7012, 1996) reported that PML-type regulatory regions occur in human tonsil tissue. The purpose of this study is to confirm their findings. Using nested polymerase chain reaction (PCR), the authors detected the regulatory region of JCV DNA in the tonsil tissue from 14 (44%) of 32 donors with tonsillitis and tonsilar hypertrophy. Sequencing of the detected regulatory regions indicated that they were identical with the archetypal regulatory regions detected previously or, in a few cases, slightly deviated from the archetype. This finding suggests not only that tonsil tissue is the potential site of initial JCV infection but also that archetypal JCV strains circulate in the human population.

Adult↗

PubMed2005

Highly active antiretroviral therapy access and neurological complications of human immunodeficiency virus infection: impact versus resources in Brazil.

Currently, there are almost 600,000 human immunodeficiency virus (HIV)-infected individuals in Brazil. From 1984 to 2004, 362,364 acquired immunodeficiency virus (AIDS) cases were officially reported and 155,000 patients are under highly active antiretroviral therapy (HAART) treatment. Like in developed countries, universal access to treatment in Brazil has definitively changed both mortality and morbidity of AIDS. Today, the median survival time is 58 months, with a 2-year survival of 63%, versus 18 months before HAART. As expected, the incidence of nervous system opportunistic infectious diseases and tumors has also decreased in Brazil. However, few Brazilian reports about neurological manifestations of HIV infection are available, particularly after the beginning of more effective antiretroviral therapy. Autopsy series report that toxoplasmosis is the most prevalent neurological disease, followed by cryptococcosis and HIV encephalitis. A much lower incidence of progressive multifocal leukoencephalopathy has been described in Brazil than in reports from developed countries. A possibility for this discrepancy could be differences in terms of JC virus (JCV) isolates or even the interactions between JCV and local HIV strains. Some particularities about the involvement of the nervous system in Brazilian patients are worthy of note, such as the occurrence of central nervous system involvement in chronic Chagas' disease in patients with AIDS, and the concomitance of leprosy and HIV infection. National surveillance of neurological manifestations of HIV infection is needed to ascertain the real impact of HAART on nervous system diseases associated with AIDS in Brazil.

AIDS-Related Opportunistic Infections↗

PubMed2005

Central nervous system opportunistic infections in developed countries in the highly active antiretroviral therapy era.

A marked decrease in incidence has been observed for most central nervous system (CNS) opportunistic infections (OIs) after the use of highly active antiretroviral therapy (HAART) in developed countries. However, the spectrum of these OIs in acquired immunodeficiency syndrome (AIDS) patients has remained almost unchanged. CNS toxoplasmosis, cryptococcosis, tuberculosis, and progressive multifocal leukoencephalopathy (PML) remain the most frequent ones. Primary CNS lymphoma should be included in the differential diagnosis of all cases with focal lesions. Final diagnosis is currently made by combining neuroimaging techniques (single-photon emission computed tomography [SPECT], positron emission tomography [PET], magnetic resonance imaging [MRI] and/or computed tomography [CT] scan) and molecular studies of cerebrospinal fluid (CSF) and therapeutical response. Stereotactic biopsy should only be performed in the case of atypical lesions or nonresponse to recommended treatments. After treatment of the acute phase, lifelong maintenance therapy is necessary to prevent OI recurrences. Once HAART is initiated, some patients can develop a clinical worsening of some CNS OIs with or without atypical neuroimaging manifestations. This paradoxical worsening is known as the immune reconstitution inflammatory syndrome (IRIS) and it results from reconstitution of the immune system's ability to recognize pathogens/antigens in patients with prior OIs and low CD4+ T-cell counts. In this context, IRIS can be seen in patients with CNS cryptococcosis, tuberculosis, or PML. On the other hand, HAART-induced immune reconstitution can improve the prognosis of some untreatable diseases such as PML, and can allow maintenance therapy of some CNS OI to be safely discontinued in patients with high and sustained CD4+ T-cell response.

AIDS-Related Opportunistic Infections↗

PubMed2005

Genotypes of JC virus, DNA of cytomegalovirus, and proviral DNA of human immunodeficiency virus in eyes of acquired immunodeficiency syndrome patients.

JC virus (JCV) is a human polyomavirus that exists in at least eight different genotypes as a result of coevolution with different human populations all over the world. Well adapted to its host, it usually persists in the kidneys and possibly the brain. If the host becomes immunodeficient, JCV can cause the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). There is increasing evidence that JCV is transactivated by cytomegalovirus (CMV) and the human immunodeficiency virus (HIV). Both CMV and HIV can infect the retina of acquired immunodeficiency syndrome (AIDS) patients, causing severe necrosis in the case of CMV retinitis or a mild HIV-associated vasculopathy, with bleeding and cotton wool spots. The authors therefore investigated by polymerase chain reaction (PCR) whether DNA of these three viruses was detectable in paraffin-embedded eyes of AIDS patients with a clinical history of CMV retinitis. From a total of 65 eyes, JCV was detected in 21 (32%). Thirty-six (55%) were positive for CMV and 6 (9%) for proviral DNA of HIV. JCV and CMV were found in 13 eyes, JCV and HIV in 3 eyes, CMV and HIV in 1 eye, and DNA from all three viruses in 1 eye. The JCV genotypes were types 1A, 2A, 2E, 3, and 4. In 21 eyes of patients without AIDS, only one sample was JCV positive. In conclusion, JCV DNA can be detected in ocular tissue of AIDS patients at a significantly higher level than in eyes of nonimmunosuppressed patients. Further investigations will help to decide if JCV contributes to the retinopathy caused by CMV and HIV.

Acquired Immunodeficiency Syndrome↗

PubMed2006

JC virus in the Irish population: significant increase of genotype 2 in immunocompromised individuals.

The human polyomavirus JC virus (JCV) is ubiquitous and can be shed in the urine of more than 40% of the healthy population. Amplification and sequencing of JCV from urine has allowed a distinctive map of the distribution of JCV genotypes worldwide. To define the frequency of JCV urinary excretion and genotype distribution in Ireland, urines from 121 healthy individuals and from 94 immunocompromised individuals (human immunodeficiency virus [HIV]-positive patients and rheumatoid arthritis patients) were collected. JCV DNA was detected by polymerase-chain reaction (PCR) with subsequent nucleotide sequencing of a fragment of the major capsid protein (VP1). JCV was detected in 20.7% of healthy individuals and was found significantly more often in the urine of HIV-positive patients (54.2%; P < .001) and rheumatoid arthritis patients (54.4%; P < .001). In healthy Irish individuals genotype 1 was the predominant genotype in 62.5%, followed by genotype 4 in 16.7% and genotype 2 in 12.5%. In contrast, genotype 2 was significantly more often isolated from the urine of both HIV-positive patients (60%) and rheumatoid arthritis patients (54.4%; P < .01). The pattern of genotype distribution among healthy Irish individuals is in agreement with data reported from other European countries, whereas the overall level of JCV urinary excretion is lower. Previous studies have found genotype 2 significantly more often in cerebrospinal (CSF) samples of patients with progressive multifocal leukoencephalopathy (PML). Here the authors report an increased frequency of genotype 2 in urine samples of immunocompromised non-PML patients. This finding further underlines the hypothesis that there could be biologic differences between JCV genotypes.

Amino Acid Sequence↗

PubMed2001

Bk virus: a clinical review.

We present a review of the clinically oriented literature about BK virus, a relative of JC virus, which is the etiologic agent of progressive multifocal leukoencephalopathy (PML). The kidney, lung, eye, liver, and brain have been proposed as sites of BK virus-associated disease, both primary and reactivated. BK virus has also been detected in tissue specimens from a variety of neoplasms. We believe that BK virus is most often permissively present in sites of disease in immunosuppressed patients, rather than being an etiologic agent that causes symptoms or pathologic findings. There is, however, strong evidence for BK virus-associated hemorrhagic cystitis and nephritis, especially in recipients of solid organ or bone marrow transplants. Now that BK virus can be identified by use of specific and sensitive techniques, careful evaluation of the clinical and pathologic presentations of patients with BK virus will allow us to form a clearer picture of viral-associated pathophysiology in many organ systems.

Animals↗