Background: The human neurotropic polyomavirus, JCV, contains an open reading frame within the late region of the viral genome that encodes a 71-amino-acid protein, agnoprotein. Because accumulating ...evidence supports an association between JCV infection and human brain tumors, including medulloblastomas, we assessed the presence of JCV Agno gene sequences and the expression of agnoprotein in a series of 20 well-characterized medulloblastomas. Methods: Formalin-fixed, paraffin-embedded tumor tissue samples were used for Agno gene amplification and for immunohistochemical analysis. Adjacent sections were stained with an antibody to agnoprotein and with antibodies to cellular structural and regulatory proteins, including the JCV early gene product, T antigen. Results: Analysis of amplified DNA from paraffin-embedded samples revealed the presence of the Agno gene in 11 (69%) of 16 samples. Immunohistochemical analysis showed cytoplasmic localization and widespread distribution of agnoprotein in the neoplastic cells in 11 (55%) of 20 samples. The JCV early gene product, T antigen, was present in the nucleus of some, but not all, of the neoplastic cells. Some medulloblastoma samples that expressed agnoprotein had no sign of T-antigen expression. p53 was detected in only six of the 11 tumors in which agnoprotein was expressed. None of the 20 samples showed expression of the viral late capsid proteins, ruling out productive infection of the tumor cells with JCV. Conclusions: Our data provide evidence that the JCV late gene encoding the auxiliary agnoprotein is expressed in tumor cells. The finding of agnoprotein expression in the absence of T-antigen expression suggests a potential role for agnoprotein in pathways involved in the development of JCV-associated medulloblastomas.
Many infectious agents can cause central nervous system (CNS) diseases in humans. Since microbial agents infecting CNS are numerous and have different features, conventional laboratory tests may not ...be sensitive enough to identify and characterise viruses and bacteria in human biological specimens. Thus, the need to define methods for the diagnosis of infectious neurological diseases, such as progressive multifocal leukoencephalopathy (PML), is urgent, in order to improve the outcome of the diseases with rapid and accurate detection of the pathogens.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
JC virus (JCV) is a human polyomavirus that causes progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease that mainly affects immunocompromised subjects. Since its discovery, ...PML has been considered a rapidly progressing fatal disease; however, amino acid substitutions in the capsid viral protein have recently been tentatively associated with changes in PML clinical course. In order to provide more insight to PML pathogenesis and identify potential prognostic markers, seven cerebrospinal fluid (CSF) samples and four brain autopsy samples were collected from patients afflicted with PML with different clinical courses (fast- and slow-progressing), and the JCV VP1 coding region was amplified, cloned, and sequenced. In addition, urine samples were collected and analyzed from nine patients with PML or other neurological diseases (ONDs) as a control group. Sequencing analysis of the genomic region encoding the VP1 outer loops revealed polymorphic residues restricted to four positions (74, 75, 117, and 128) in patients with slow PML progression, whereas no significant mutation was found in JCV isolated from urine. Collectively, these data show that JCV VP1 loop mutations are associated with a favorable prognosis for PML. It is therefore possible that slower progression of PML may be related to the emergence of a less virulent JCV strain with a lower replication rate.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Following the development of progressive multifocal leukoencephalopathy (PML) in two multiple sclerosis (MS) patients treated with natalizumab and interferon-β (IFNβ), a possible correlation between ...JC virus (JCV), the etiological agent of PML, and MS has received heightened interest. In particular, attention has focused on assessing whether IFNβ treatment could affect the replication of JCV and thus its frequency in the peripheral blood of MS patients and whether the presence of JCV DNA in peripheral blood could be a predictive marker of the risk of developing PML. In order to answer to these questions, peripheral blood samples were collected from 59 INFβ-treated, 39 untreated relapsing-remitting MS patients, and 98 healthy controls (HCs) and JCV DNA levels were determined and quantified by means of a real-time polymerase chain reaction (Q-PCR) assay. Overall, no differences were found in the presence or viral load of JCV DNA of MS patients and the HCs, but JCV DNA was significantly less frequent in the peripheral blood of IFNβ-treated patients (13.6%) compared to the untreated MS patients (46.1%) and the healthy controls (28.6%). These results suggest that the presence of JCV in the blood of MS patients cannot be considered as a marker or a risk factor for PML development. In addition, they indicate that treatment with INFβ can lead to the reduction of presence of the JCV genome in the peripheral blood of MS patients and, thus, that this drug probably does not increase the risk of PML in MS patients treated with IFNβ.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract A dynamic equilibrium between proliferation and programmed cell death (PCD) of auto-reactive T lymphocytes plays a pivotal role in the prevention of autoimmune diseases. We analyzed T ...lymphocytes myelin basic protein (MBP)-specific PCD and proliferation in demyelinating diseases. Results showed that MBP-specific PCD was significantly decreased in CD4+ and CD8+ T lymphocytes of progressive multifocal leukoencephalopathy (PML), not determined leukoencephalopathy (NDLE), and acute MS (AMS) patients compared to patients with stable MS (SMS) and healthy controls. MBP-specific proliferation/PCD rates were high in CD4+ T lymphocytes of PML, NDLE, and AMS patients, and in CD8+ T cells of PML and AMS individuals alone. Alterations of the balance between MBP-specific proliferation and PCD are present in demyelinating diseases and could play a major role in the pathogenesis of these diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Progressive Multifocal Leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system (CNS) caused by JC virus (JCV), a human polyomavirus that can lytically infect ...and destroy the oligodendrocites in immunosuppressed individuals. After the introduction of highly active antiretroviral therapy (HAART) for AIDS treatment, a PML-like leukoencephalopathy, known as non-determined leukoencephalopathy (NDLE), has also been observed. Since a number of host genetic factors have been identified as having an impact on susceptibility to HIV-1 infection and in the progression to AIDS and death, in this work we analysed the pattern of distribution of different chemokine and chemokine receptor polymorphisms that seem to be involved in HIV+ neurological diseases. The CCR5, RANTES, CCR2 and SDF1 genes were molecularly analysed in 84 HIV+ HAART treated subjects: 55 without neurological disorders (HIV+), 12 HIV+ NDLE and 17 HIV+ PML patients. The RANTES −403 G/A polymorphism was significantly associated with NDLE. These data suggest that mutation of the RANTES allele can predispose to the induction of demyelination similarly to what has been observed in Multiple Sclerosis (MS) and may suggest a possible explanation for the development of leukoencephalopathy without detection of JCV.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
JC virus (JCV) is the etiological agent of progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease of the central nervous system (CNS). During the acquired immunodeficiency ...syndrome (AIDS) epidemic, it was the cause of the death in up to 8% of AIDS patients. The genomic organization of JCV and, in particular, the hypervariability of the transcriptional control region (TCR), a regulatory noncoding region, are well known. Given that the TCR plays a central role in the viral replication of JCV, a crucial role in the determination of the neurotropism and in the pathogenic capabilities of the virus is also suspected. Here the authors describe a case of PML that did not respond to highly active antiretroviral therapy (HAART) therapy. There was a simultaneous presence of JCV strains with four different TCR structures in urine, peripheral blood cells, serum, and cerebrospinal fluid (CSF) samples. These data confirmed that the presence of the archetype TCR is restricted to urine, while also suggesting that the degree of the rearrangement varies and increases from the peripheral blood to CSF.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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