Viral variant nucleotide sequences help expose leukocytic positioning in the JC virus pathway to the CNS

Jensen, Philip J.; Major, Eugene O.

doi:10.1002/jlb.65.4.428

Cited by 47 publications

(30 citation statements)

References 87 publications

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“…All colon cancer specimens, but not the adjacent nonneoplastic tissues, were characterized by the presence of a strain with the sequence of the Mad-1 TCR but with the deletion of one 98-bp sequence. This variant was previously found in kidneys and brains of infected patients (6), and in bone marrow and brain tissue from one PML patient (9). According to previous reports, an artificial mutant strain, pM1⌬98, that contains one 98-bp repeat obtained by deleting the late 98-bp sequence from Mad-1, consistently demonstrates less viability and lower replication rates than the Mad-1 strain in PHFG cells (3).…”

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confidence: 60%

Mad-1 Is the Exclusive JC Virus Strain Present in the Human Colon, and Its Transcriptional Control Region Has a Deleted 98-Base-Pair Sequence in Colon Cancer Tissues

Ricciardiello

Chang

Laghi

et al. 2001

J Virol

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JC virus (JCV), along with other members of the polyomavirus family, encodes a class of highly conserved proteins, T antigens, that are capable of inducing aneuploidy in cultured cells. We have previously isolated T-antigen DNA variants of JCV from both colon cancer tissues and the corresponding nonneoplastic gastrointestinal tissues, raising new questions about the role of JCV in the development of chromosomal instability of the colon. Based on the sequence of the transcriptional control region (TCR), JCV can be classified as archetype or tandem repeat variants. Among the latter, Mad-1, the prototype virus first isolated from a patient with progressive multifocal leukoencephalopathy, is characterized by lacking the 23-and 66-bp sequences that are present in the archetype and by duplication of a 98-bp sequence. In this study, we evaluated differences in the TCR of JCV isolated from colon cancer tissues and nonneoplastic epithelium. To characterize JCV variants, we first treated eight pairs of DNA samples from colon cancers and noncancerous tissue with topoisomerase I and then amplified and cloned the JCV TCR. We obtained 285 recombinant clones from the JCV TCR, 157 from nonneoplastic samples, and 128 from colon cancer tissues. Of these clones, 262 spanned the length of the JCV Mad-1 TCR: 99.3% from nonneoplastic samples and 82.8% from colon cancer tissues. In sequencing 54 clones in both directions, we did not find archetype JCV either in the nonneoplastic tissue or in the cancer samples. From all colon cancer tissues, 18 clones had a deletion of one 98-bp tandem repeat. This deleted strain was not detected in any of the nonneoplastic tissues (14 versus 0% [ 2 ‫؍‬ 23.6; P < 0.001]). Our study demonstrates that the only JCV strain present in the human colon is Mad-1, and the variant with a single 98-bp sequence is found exclusively in the cancer tissues. This strain may be involved in the development of chromosomal instability.The human polyomavirus JC virus (JCV) infects a large proportion of the population worldwide (23). The initial infection is unapparent, but subsequently JCV establishes a latent infection, becoming reactivated when the immune system is impaired (8). The JCV genome is double-stranded, negatively supercoiled circular DNA that consists of early and late coding regions separated by two noncoding regions at both the 5Ј and 3Ј ends. Within the noncoding sequences is the transcriptional control region (TCR), which contains the promoter and enhancer for the early and late proteins; the intergenic region separates the 3Ј regions of T antigen and the capsid protein, VP1.T antigen is an oncogenic protein capable of transforming mammalian cells by interacting with cellular proteins such as p53 and the Rb family proteins (5, 21). T antigen also has ATPase and helicase activities, the latter of which may eventually contribute to chromosomal breakage and recombination (7). We have recently reported the presence of JCV T-antigen DNA sequences in nonneoplastic gastrointestinal tissues, colon cancer samples,...

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confidence: 60%

Mad-1 Is the Exclusive JC Virus Strain Present in the Human Colon, and Its Transcriptional Control Region Has a Deleted 98-Base-Pair Sequence in Colon Cancer Tissues

Ricciardiello

Chang

Laghi

et al. 2001

J Virol

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“…Archetype is rarely associated with PML tissue (554). The consistent isolation of tandem repeat-like NCCR sequences including the 98-bp tandem repeat in tissues obtained from PML patients strongly suggests the importance of this structure in viral pathogenesis (154,214,317,322,510). The prototype and prototype-like sequence variants are generally found in PML tissue, while kidney-and urine-derived NCCR sequences are normally homologous to archetype.…”

Section: Analysis Of the Viral Genomementioning

confidence: 91%

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

et al. 2012

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SUMMARY Progressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for which there is currently no effective treatment. Lytic infection of oligodendrocytes in the brain leads to their eventual destruction and progressive demyelination, resulting in multiple foci of lesions in the white matter of the brain. Before the mid-1980s, PML was a relatively rare disease, reported to occur primarily in those with underlying neoplastic conditions affecting immune function and, more rarely, in allograft recipients receiving immunosuppressive drugs. However, with the onset of the AIDS pandemic, the incidence of PML has increased dramatically. Approximately 3 to 5% of HIV-infected individuals will develop PML, which is classified as an AIDS-defining illness. In addition, the recent advent of humanized monoclonal antibody therapy for the treatment of autoimmune inflammatory diseases such as multiple sclerosis (MS) and Crohn's disease has also led to an increased risk of PML as a side effect of immunotherapy. Thus, the study of JCV and the elucidation of the underlying causes of PML are important and active areas of research that may lead to new insights into immune function and host antiviral defense, as well as to potential new therapies.

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“…Furthermore, a putative role of B cells in JCV reactivation and transmigration across the blood-brain barrier has been suggested [25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Natalizumab treatment perturbs memory‐ and marginal zone‐like B‐cell homing in secondary lymphoid organs in multiple sclerosis

et al. 2011

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Natalizumab, an antibody against the a4 subunit of a4 integrins, has been approved for multiple sclerosis (MS) therapy based on its high efficacy and safety profile. However, natalizumab has been associated with the development of progressive multifocal leukoencephalopathy (PML), a disorder caused by JC virus (JCV) infection. In order to improve our understanding of the mechanism of action of natalizumab and to identify possible risk factors for PML development, we have characterized in detail the cell blood composition in MS patients treated with natalizumab for more than 30 months. Natalizumab induced the release of lymphoid-but not myeloid precursor cells, which resulted in a chronic increase of T-, NK-and particularly B cells. While the percentage of recent thymic emigrants (RTE), naïve, effector or memory T cells remained unchanged during treatment, a higher percentage of memory-and marginal zone (MZ)-like, but not of naïve B cells, was observed, which most likely is due to a decreased retention of these cells within the splenic MZ. The ability of natalizumab to influence B-cell migration and homeostasis through the splenic MZ, where JCV has been detected, adds to the list of natalizumab effects and may contribute to PML development by disseminating JCV.Key words: B cells . Multiple sclerosis . Natalizumab . Progressive multifocal leukoencephalopathy Supporting Information available online Introduction Natalizumab, a monoclonal antibody against the a4 subunit (CD49d) of a4 integrins (a4b1 and a4b7), has been approved for multiple sclerosis (MS) therapy based on its high efficacy and good safety profile. The a4b1 integrin is expressed by all leukocytes except neutrophils and serves as an adhesion molecule mediating attachment to endothelial cells. Natalizumab prevents transmigration of leukocytes across the blood-brain barrier by blocking a4b1 integrin/vascular cell adhesion molecule-1 (VCAM-1) interaction [1][2][3][4][5]. a4b1 integrin also serves as a retention signal for hematopoietic precursor cells in the BM, and consequently it has been demonstrated that natalizumab mobilizes hematopoietic precursor cells from the BM [6][7][8]. Natalizumab treatment also induces significant phenotypic changes in the immune cell composition of peripheral blood such as an increase Eur. J. Immunol. 2012. 42: 790-798 790 in T-, NK-and especially B cells and a decrease in monocytes [9][10][11][12]. These changes have been attributed to a higher release of hematopoietic precursor cells from the BM as well as a reduced migration of leukocytes into the central nervous system (CNS). However, since a4 integrin ligands are also expressed in secondary lymphoid tissues, such as spleen and gut-associated lymphoid tissue, natalizumab may influence the immune cell composition in the blood by affecting homeostasis, homing and migration of leukocytes through secondary lymphoid organs as well.Natalizumab treatment can lead to progressive multifocal leukoencephalopathy (PML), a demyelinating disorder of the CNS caused by JC virus (JCV...

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Viral variant nucleotide sequences help expose leukocytic positioning in the JC virus pathway to the CNS

Cited by 47 publications

References 87 publications

Mad-1 Is the Exclusive JC Virus Strain Present in the Human Colon, and Its Transcriptional Control Region Has a Deleted 98-Base-Pair Sequence in Colon Cancer Tissues

Mad-1 Is the Exclusive JC Virus Strain Present in the Human Colon, and Its Transcriptional Control Region Has a Deleted 98-Base-Pair Sequence in Colon Cancer Tissues

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

Natalizumab treatment perturbs memory‐ and marginal zone‐like B‐cell homing in secondary lymphoid organs in multiple sclerosis

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