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Journal of Immunotherapy (Hagerstown,... Mar 1997A large body of evidence supports the hypothesis that an infectious agent is involved in the etiology of acute lymphoblastic leukemia (ALL) in children in the 2-5-year... (Review)
Review
A large body of evidence supports the hypothesis that an infectious agent is involved in the etiology of acute lymphoblastic leukemia (ALL) in children in the 2-5-year age range. To explain these data, it has been proposed that some cases of pediatric ALL arise as a rare response to a common childhood infection, and that the leukemia-inducing potential of the agent is related to the timing of infection, with a greater leukemogenic effect for later infections compared with those occurring during infancy. An alternative model for the etiology of a subset of childhood ALL is proposed that places the critical infectious event during pregnancy rather than early childhood. In this model, the etiologic agent causes a primary infection in the mother that is transmitted to the fetus, and as a consequence of this in utero infection, the child is at increased risk of developing ALL before the age of 5 years. The characteristics that the causative infectious agent of childhood ALL occurring in the 2-5-year age range should possess include (a) ability to induce genomic instability; (b) specific effects on B lymphocytes and not on T lymphocytes; (c) higher rates of infection in regions with lower socioeconomic status; (d) limited general oncogenic potential; (e) minimal symptoms associated with the primary infection; and (f) ability to cross the placenta and infect the fetus, but not cause severe fetal abnormalities. A candidate virus meeting many of these criteria is the JC virus, a member of the polyomavirus family. Implications of the possible etiologic role of JC virus for some cases of childhood ALL (especially those with hyperdiploid leukemia cells) are discussed.
Topics: Adult; Child; Female; Genome; Humans; JC Virus; Polyomavirus Infections; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pregnancy; Pregnancy Complications, Infectious; Tumor Suppressor Protein p53; Tumor Virus Infections
PubMed: 9087381
DOI: 10.1097/00002371-199703000-00001 -
Parkinsonism & Related Disorders Apr 2023
Topics: Humans; Multiple System Atrophy; JC Virus; alpha-Synuclein; Brain
PubMed: 36935321
DOI: 10.1016/j.parkreldis.2023.105358 -
Journal of Neurovirology 2003The JC virus early mRNA is alternatively spliced to yield five transcripts that encode large T antigen, small t antigen, T'(135), T'(136), and T'(165). The splicing... (Review)
Review
The JC virus early mRNA is alternatively spliced to yield five transcripts that encode large T antigen, small t antigen, T'(135), T'(136), and T'(165). The splicing process is regulated differentially in transformed versus lytically infected cells and temporally during the course of a productive infection. The authors have identified a potential exonic splicing enhancer near the 3' end of the early viral mRNA that, when mutated, results in altered splice site usage. The authors have only recently begun investigating the function of the three T' proteins using genetic and biochemical approaches. These studies indicate that the T' proteins enhance viral DNA replication and bind differentially to the pRB family of cellular tumor suppressor proteins in vitro. Using a G418 selection scheme, the authors have created cell lines that express either T antigen or each of the T' proteins individually. Preliminary analyses of these lines suggest that T antigen may induce apoptosis in rodent cells, an activity that may be blocked by other JC virus early proteins. Furthermore, examination of protein-protein interactions within the G418-selected cells reveal differences in binding of the viral proteins to the pRB family members relative to that seen in vitro.
Topics: Alternative Splicing; Antigens, Viral, Tumor; Humans; JC Virus; Polyomavirus Infections; Tumor Virus Infections
PubMed: 12709866
DOI: 10.1080/13550280390195270 -
Oncogene Aug 2006Human polyomaviruses (JC virus, BK virus and simian virus 40) are causative agents of some human diseases and, interestingly, are involved in processes of cell... (Review)
Review
Human polyomaviruses (JC virus, BK virus and simian virus 40) are causative agents of some human diseases and, interestingly, are involved in processes of cell transformation and oncogenesis. These viruses need the cell cycle machinery of the host cell to complete their replication; so they evolved mechanisms that can interfere with the growth control of infected cells and force them into DNA replication. The retinoblastoma family of proteins (pRb), which includes pRb/p105, p107 and pRb2/p130, acts as one of the most important regulators of the G1/S transition of the cell cycle. Rb proteins represent an important target for viral oncoproteins. Early viral T antigens can bind all members of the pRb family, promoting the activation of the E2F family of transcription factors, thus inducing the expression of genes required for the entry to the S phase. The interaction between early viral antigens and cell cycle regulators represents an important mechanism through which viruses deregulate cell cycle and lead to cell transformation. In this review, we will discuss the effects of the interaction between large T antigen and Rb proteins in JC virus-mediated oncogenesis.
Topics: Antigens, Polyomavirus Transforming; BK Virus; Brain Neoplasms; Cell Cycle; Gene Expression Regulation, Viral; Humans; JC Virus; Retinoblastoma Protein; Simian virus 40; Transcription, Genetic; Tumor Virus Infections
PubMed: 16936750
DOI: 10.1038/sj.onc.1209681 -
Journal of Neurovirology Oct 2008
Topics: B-Lymphocytes; Bone Marrow; Bone Marrow Transplantation; Humans; JC Virus
PubMed: 18925491
DOI: 10.1080/13550280802348222 -
International Journal of Molecular... Apr 1998JC virus, a human neurotropic polyomavirus, is the established etiologic agent of the fatal demyelinating disease, progressive multifocal leukoencephalopathy, which... (Review)
Review
JC virus, a human neurotropic polyomavirus, is the established etiologic agent of the fatal demyelinating disease, progressive multifocal leukoencephalopathy, which usually affects individuals with defects in cell-mediated immunity. Cytolytic destruction of oligodendrocytes, the myelin-producing cells of the central nervous system is attributed as the mechanism by which JCV induces demyelination. PML was at one time a rare complication however it is now a much more common disease affecting patients of all ages due to the prevalence of AIDS. Of interest, in vitro evidence points to a cooperative interaction between JCV and HIV-1, via the HIV-1 regulatory protein, Tat. In addition, JCV has been demonstrated to induce tumors of neural origin in several animal models, including rodents and non-human primates, and several clinical reports have suggested a possible association between JCV and glial-origin tumors in humans. The viral regulatory protein, T-antigen, which has been shown to play a key role in orchestrating the events of the viral lytic cycle, is also capable of altering cellular functions, by nature of its direct interaction with cellular regulatory proteins and by its effect on cellular transcription. In this review, we discuss clinical aspects of PML, the ability of JCV to induce tumors in animal models, and the ability of JCV T-antigen to alter cellular function in vitro.
Topics: AIDS-Related Opportunistic Infections; Animals; Central Nervous System Neoplasms; Humans; JC Virus; Leukoencephalopathy, Progressive Multifocal; Virus Activation
PubMed: 9852278
DOI: 10.3892/ijmm.1.4.647 -
Advances in Experimental Medicine and... 2006Primary contact with the human polyomaviruses (HPV) is followed by lifelong persistence of viral DNA in its host. The most prominent organs affected are the kidney, the... (Review)
Review
Primary contact with the human polyomaviruses (HPV) is followed by lifelong persistence of viral DNA in its host. The most prominent organs affected are the kidney, the Central Nervous System (CNS)and the hematopoietic system. Under impairment of immune competence limited activation of virus infection can be followed by prolonged virus multiplication, severe destruction of tissue and disease. The mechanisms responsible for activation episodes of the asymptomatic persistent infection are not understood and questions on cellular localization, routes of dissemination of HPV infection and its activation are controversially discussed. The type of interaction of HPVs with target organs and patients groups is highly differentiated. Organ-specific activation above basic level argues for strong dependence on the respective immune states of risk group patients. However, since immune impairment generally plays an important role in the activation of polyomavirus infection, amplification of virus deoxyribonucleic acid (DNA) and activation of virus replication is also a normal event that is probably subject to immunomodulation in the healthy individual. It also becomes clear that BKV and JCV infection is differentially regulated by mechanisms depending on the balance of immune control as well as on organ-specific signalling.
Topics: BK Virus; DNA, Viral; Humans; JC Virus; Polyomavirus Infections; Tissue Distribution
PubMed: 16626031
DOI: 10.1007/0-387-32957-9_8 -
Journal of Neurovirology Feb 2022Progressive multifocal leukoencephalopathy (PML) is a frequent neurological complication in immunosuppressed patients. PML is caused by the JC virus (JCV), a neurotropic...
Progressive multifocal leukoencephalopathy (PML) is a frequent neurological complication in immunosuppressed patients. PML is caused by the JC virus (JCV), a neurotropic DNA polyomavirus that infects oligodendrocytes and astrocytes, causing inflammation and demyelination which lead to neurological dysfunction. The pathogenesis of PML is poorly understood due to the lack of in vitro or animal models to study mechanisms of disease as the virus most efficiently infects only human cells. We developed a human-derived brain organotypic system (also called brain organoid) to model JCV infection. The model was developed by using human-induced pluripotent stem cells (iPSC) and culturing them in 3D to generate an organotypic model containing neurons, astrocytes, and oligodendrocytes which recapitulates aspects of the environment of the human brain. We infected the brain organoids with the JCV MAD4 strain or cerebrospinal fluid of a patient with PML. The organoids were assessed for evidence of infection by qPCR, immunofluorescence, and electron microscopy at 1, 2, and 3 weeks post-exposure. JCV infection in both JCV MAD4 strain and PML CSF-exposed brain organoids was confirmed by immunocytochemical studies demonstrating viral antigens and electron microscopy showing virion particles in the nuclear compartment of oligodendrocytes and astrocytes. No evidence of neuronal infection was visualized. Infection was also demonstrated by JCV qPCR in the virus-exposed organoids and their media. In conclusion, the brain organoid model of JCV infection establishes a human model suitable for studying the mechanisms of JCV infection and pathogenesis of PML and may facilitate the exploration of therapeutic approaches.
Topics: Animals; Brain; DNA, Viral; Humans; JC Virus; Leukoencephalopathy, Progressive Multifocal; Organoids; Polyomavirus Infections
PubMed: 35239145
DOI: 10.1007/s13365-022-01062-7 -
Uirusu Jun 2006Human polyomavirus JC (JCV) is a causative agent for progressive multifocal leukoencephalopathy, a fatal demyelinating disorder. The viruses form intranuclear viral... (Review)
Review
Human polyomavirus JC (JCV) is a causative agent for progressive multifocal leukoencephalopathy, a fatal demyelinating disorder. The viruses form intranuclear viral inclusions in infected oligodendrocytes. The outer capsid of JCV is thought to be composed of 360 molecules of major capsid protein VP1, and minor capsid proteins VP2 and VP3 in an appropriate ratio. However, the regulatory mechanisms of gene expression for the capsid proteins, their nuclear transport, and formation of viral inclusions are not well understood. We have recently clarified the following regarding the mechanism underlying JCV virion assembly; (i) major and minor capsid proteins are synthesized from messenger RNAs, the expression ratio of which is determined by alternative splicing, (ii) messenger RNAs for the major and minor capsid proteins are polycistronic, and their translation occurs downstream of the regulatory protein, agnoprotein, (iii) major and minor capsid proteins are translocated to the nucleus in a cooperative manner and accumulate at the dot-shaped intranuclear structures called promyelocytic leukemia nuclear bodies (PML-NBs), (iv) efficient viral replication can occur at the PML-NBs, where capsid assembly is likely to be associated with viral DNA replication. PML-NBs are the sites for expression of important nuclear functions for the host cells. The finding that the target of JCV infection is the PML-NB may contribute greatly to our understanding of the mechanism underlying cellular degeneration, which occurs after the formation of intranuclear viral inclusions.
Topics: Capsid Proteins; DNA Replication; DNA, Viral; Humans; Intranuclear Inclusion Bodies; JC Virus; Leukoencephalopathy, Progressive Multifocal; Protein Transport; RNA, Messenger; RNA, Viral; Virion; Virus Replication
PubMed: 17038808
DOI: 10.2222/jsv.56.17 -
Clinical Microbiology Reviews Jan 1992Studies of the pathogenesis and molecular biology of JC virus infection over the last two decades have significantly changed our understanding of progressive multifocal... (Review)
Review
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.
Topics: Animals; Base Sequence; Brain; Brain Diseases; Brain Neoplasms; Cell Line; Cricetinae; Demyelinating Diseases; Genes, Viral; Humans; JC Virus; Mice; Molecular Sequence Data; Tumor Virus Infections
PubMed: 1310438
DOI: 10.1128/CMR.5.1.49