Lack of disease-specific amino acid changes in the viral proteins of JC virus isolates from the brain with progressive multifocal leukoencephalopathy

2000 ◽  
Vol 145 (10) ◽  
pp. 2173-2182 ◽  
Author(s):  
A. Kato ◽  
C. Sugimoto ◽  
H.-Y. Zheng ◽  
T. Kitamura ◽  
Y. Yogo
Keyword(s):  
Amino Acid ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Jc Virus ◽  
Viral Proteins ◽  
Specific Amino Acid ◽  
The Brain ◽  
Virus Isolates ◽  
Disease Specific

Stability of JC Virus Coding Sequences in a Case of Progressive Multifocal Leukoencephalopathy in Which the Viral Control Region Was Rearranged Markedly

2004 ◽  
Vol 128 (3) ◽  
pp. 275-278
Author(s):  
Huai-Ying Zheng ◽  
Yukiharu Yasuda ◽  
Shunichi Kato ◽  
Tadaichi Kitamura ◽  
Yoshiaki Yogo
Keyword(s):  
Amino Acid ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Control Region ◽  
Jc Virus ◽  
Viral Proteins ◽  
Structural Features ◽  
Viral Control ◽  
Coding Sequences ◽  
Control Sequences ◽  
Control Regions

Abstract Context.—It is generally accepted that JC virus variants in the brains of patients with progressive multifocal leukoencephalopathy are generated from archetypal strains through sequence rearrangement (deletion and duplication, or deletion alone) in the control region. This change is thought to occur during persistence of JC virus in patients. Objective.—The present study was performed to ascertain whether amino acid substitution in the viral proteins is involved in the generation and propagation of JCV variants with rearranged control regions. Design.—Many complete JC DNA clones were established from brain tissues (cerebellum, occipital lobe, and brainstem) autopsied in a case of progressive multifocal leukoencephalopathy in which multiple distinct control sequences were detected. Control and coding sequences were determined and compared among the JC DNA clones. Results.—Twenty-eight control-region and 20 coding sequences of JC virus were compared. Five rearranged control sequences were detected, but they could be classified into 3 groups that shared common structural features. Viral coding sequences were identical among clones with different control regions and among clones derived from different brain regions. Conclusion.—In the present case, nucleotide substitution in the viral coding regions (and resultant amino acid change in the viral proteins) was involved neither in the genesis of rearranged JC virus variants nor in the proliferation of demyelinated lesions in the brain.

scholarly journals Deep-Sequence Identification and Role in Virus Replication of a JC Virus Quasispecies in Patients with Progressive Multifocal Leukoencephalopathy

2016 ◽  
Vol 91 (1) ◽  
Author(s):  
Kenta Takahashi ◽  
Tsuyoshi Sekizuka ◽  
Hitomi Fukumoto ◽  
Kazuo Nakamichi ◽  
Tadaki Suzuki ◽  
...  
Keyword(s):  
Amino Acid ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Viral Replication ◽  
Virus Replication ◽  
Amino Acid Substitution ◽  
Jc Virus ◽  
Viral Proteins ◽  
T Antigen ◽  
Hek293 Cells ◽  
Next Generation

ABSTRACT JC virus (JCV) is a DNA virus causing progressive multifocal leukoencephalopathy (PML) in immunodeficient patients. In the present study, 22 genetic quasispecies with more than 1.5% variant frequency were detected in JCV genomes from six clinical samples of PML by next-generation sequencing. A mutation from A to C at nucleotide (nt) 3495 in JCV Mad1 resulting in a V-to-G amino acid substitution at amino acid (aa) position 392 of the large T antigen (TAg) was identified in all six cases of PML at 3% to 19% variant frequencies. Transfection of JCV Mad1 DNA possessing the V392G substitution in TAg into IMR-32 and human embryonic kidney 293 (HEK293) cells resulted in dramatically decreased production of JCV-encoded proteins. The virus DNA copy number was also reduced in supernatants of the mutant virus-transfected cells. Transfection of the IMR-32 and HEK293 cells with a virus genome containing a revertant mutation recovered viral production and protein expression. Cotransfection with equal amounts of wild-type genome and mutated JCV genome did not reduce the expression of viral proteins or viral replication, suggesting that the mutation did not have any dominant-negative function. Finally, immunohistochemistry demonstrated that TAg was expressed in all six pathological samples in which the quasispecies were detected. In conclusion, the V392G amino acid substitution in TAg identified frequently in PML lesions has a function in suppressing JCV replication, but the frequency of the mutation was restricted and its role in PML lesions was limited. IMPORTANCE DNA viruses generally have lower mutation frequency than RNA viruses, and the detection of quasispecies in JCV has rarely been reported. In the present study, a next-generation sequencer identified a JCV quasispecies with an amino acid substitution in the T antigen in patients with PML. In vitro studies showed that the mutation strongly repressed the expression of JC viral proteins and reduced the viral replication. However, because the frequency of the mutation was low in each case, the total expression of virus proteins was sustained in vivo. Thus, JC virus replicates in PML lesions in the presence of a mutant virus which is able to repress virus replication.

scholarly journals Pathogenesis and molecular biology of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain.

1992 ◽  
Vol 5 (1) ◽  
pp. 49-73 ◽  
Author(s):  
E O Major ◽  
K Amemiya ◽  
C S Tornatore ◽  
S A Houff ◽  
J R Berger
Keyword(s):  
B Cells ◽  
Virus Infection ◽  
Molecular Biology ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Dna Sequences ◽  
Jc Virus ◽  
Nucleoside Analogs ◽  
Sufficient Evidence ◽  
Viral Gene ◽  
The Brain

Studies of the pathogenesis and molecular biology of JC virus infection over the last two decades have significantly changed our understanding of progressive multifocal leukoencephalopathy, which can be described as a subacute viral infection of neuroglial cells that probably follows reactivation of latent infection rather than being the consequence of prolonged JC virus replication in the brain. There is now sufficient evidence to suggest that JC virus latency occurs in kidney and B cells. However, JC virus isolates from brain or kidney differ in the regulatory regions of their viral genomes which are controlled by host cell factors for viral gene expression and replication. DNA sequences of noncoding regions of the viral genome display a certain heterogeneity among isolates from brain and kidney. These data suggest that an archetypal strain of JC virus exists whose sequence is altered during replication in different cell types. The JC virus regulatory region likely plays a significant role in establishing viral latency and must be acted upon for reactivation of the virus. A developing hypothesis is that reactivation takes place from latently infected B lymphocytes that are activated as a result of immune suppression. JC virus enters the brain in the activated B cell. Evidence for this mechanism is the detection of JC virus DNA in peripheral blood lymphocytes and infected B cells in the brains of patients with progressive multifocal leukoencephalopathy. Once virus enters the brain, astrocytes as well as oligodendrocytes support JC virus multiplication. Therefore, JC virus infection of neuroglial cells may impair other neuroglial functions besides the production and maintenance of myelin. Consequently our increased understanding of the pathogenesis of progressive multifocal leukoencephalopathy suggests new ways to intervene in JC virus infection with immunomodulation therapies. Perhaps along with trials of nucleoside analogs or interferon administration, this fatal disease, for which no consensus of antiviral therapy exists, may yield to innovative treatment protocols.

scholarly journals Detection of JC Virus in Cerebrospinal Fluid (CSF) Samples from Patients with Progressive Multifocal Leukoencephalopathy but Not in CSF Samples from Patients with Herpes Simplex Encephalitis, Enteroviral Meningitis, or Multiple Sclerosis

1998 ◽  
Vol 36 (4) ◽  
pp. 1137-1138 ◽  
Author(s):  
G. Bogdanovic ◽  
P. Priftakis ◽  
A.-L. Hammarin ◽  
M. Söderström ◽  
A. Samuelson ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Herpes Simplex ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Herpes Simplex Encephalitis ◽  
Jc Virus ◽  
Inflammatory Processes ◽  
Enteroviral Meningitis ◽  
The Brain

JC virus (JCV) DNA was detected in cerebrospinal fluid (CSF) samples from patients with progressive multifocal leukoencephalopathy (PML) but not in CSF samples from patients with herpes simplex encephalitis, enteroviral meningitis, or multiple sclerosis. This suggests that inflammatory processes in the brain do not necessarily reactivate JCV, which further supports the proposal that the presence of JCV DNA in the CSF is diagnostic for PML.

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

2010 ◽  
Vol 84 (18) ◽  
pp. 9200-9209 ◽  
Author(s):  
Chen S. Tan ◽  
Laura C. Ellis ◽  
Christian Wüthrich ◽  
Long Ngo ◽  
Thomas A. Broge ◽  
...  
Keyword(s):  
Progressive Multifocal Leukoencephalopathy ◽  
Jc Virus ◽  
Regulatory Region ◽  
Study Groups ◽  
T Antigen ◽  
Hiv Positive ◽  
Hybridization Data ◽  
Virus Latency ◽  
The Brain ◽  
Hiv Negative

ABSTRACT JC virus (JCV) is latent in the kidneys and lymphoid organs of healthy individuals, and its reactivation in the context of immunosuppression may lead to progressive multifocal leukoencephalopathy (PML). Whether JCV is present in the brains or other organs of healthy people and in immunosuppressed patients without PML has been a matter of debate. We detected JCV large T DNA by quantitative PCR of archival brain samples of 9/24 (38%) HIV-positive PML patients, 5/18 (28%) HIV-positive individuals, and 5/19 (26%) HIV-negative individuals. In the same samples, we detected JCV regulatory region DNA by nested PCR in 6/19 (32%) HIV-positive PML patients, 2/11 (18%) HIV-positive individuals, and 3/17 (18%) HIV-negative individuals. In addition, JCV DNA was detected in some spleen, lymph node, bone, and kidney samples from the same groups. In situ hybridization data confirmed the presence of JCV DNA in the brains of patients without PML. However, JCV proteins (VP1 or T antigen) were detected mainly in the brains of 23/24 HIV-positive PML patients, in only a few kidney samples of HIV-positive patients, with or without PML, and rarely in the bones of HIV-positive patients with PML. JCV proteins were not detected in the spleen or lymph nodes in any study group. Furthermore, analysis of the JCV regulatory region sequences showed both rearranged and archetype forms in brain and extraneural organs in all three study groups. Regulatory regions contained increased variations of rearrangements correlating with immunosuppression. These results provide evidence of JCV latency in the brain prior to severe immunosuppression and suggest new paradigms in JCV latency, compartmentalization, and reactivation.

Occurrence of multiple JC virus variants with distinctive regulatory sequences in the brain of a single patient with progressive multifocal leukoencephalopathy

Virus Genes ◽  
1994 ◽  
Vol 8 (1) ◽  
pp. 99-105 ◽  
Author(s):  
Yoshiaki Yogo ◽  
Jing Guo ◽  
Takako Iida ◽  
Ken-Ichi Satoh ◽  
Fumiaki Taguchi ◽  
...  
Keyword(s):  
Progressive Multifocal Leukoencephalopathy ◽  
Jc Virus ◽  
Regulatory Sequences ◽  
Single Patient ◽  
The Brain
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