Analysis of JC Virus Genotype Distribution and Transcriptional Control Region Rearrangements in Human Immunodeficiency Virus-Positive Progressive Multifocal Leukoencephalopathy Patients with and without Highly Active Antiretroviral Treatment

2003 ◽  
Vol 9 (2) ◽  
pp. 42-46 ◽  
Author(s):  
Pasquale Ferrante ◽  
Serena Delbue ◽  
Elisabetta Pagani ◽  
Roberta Mancuso ◽  
Angela Marzocchetti ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Transcriptional Control ◽  
Antiretroviral Treatment ◽  
Jc Virus ◽  
Genotype Distribution ◽  
Virus Genotype ◽  
Transcriptional Control Region ◽  
Highly Active ◽  
Immunodeficiency Virus

Evidence for Involvement of Transforming Growth Factor β1 Signaling Pathway in Activation of JC Virus in Human Immunodeficiency Virus 1–Associated Progressive Multifocal Leukoencephalopathy

2004 ◽  
Vol 128 (3) ◽  
pp. 282-291
Author(s):  
Sahnila Enam ◽  
Thersa M. Sweet ◽  
Shohreh Amini ◽  
Kamel Khalili ◽  
Luis Del Valle
Keyword(s):  
Human Immunodeficiency Virus ◽  
Growth Factor ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Transforming Growth Factor ◽  
Jc Virus ◽  
Transforming Growth Factor Β1 ◽  
Immunodeficiency Virus ◽  
Acquired Immunodeficiency ◽  
Immunodeficiency Syndrome ◽  
Human Immunodeficiency Virus 1

Abstract Context.—Progressive multifocal leukoencephalopathy is a fatal demyelinating disease of the central nervous system frequently seen in patients with impaired immune systems, particularly acquired immunodeficiency syndrome. JC virus (JCV), a human neurotropic polyomavirus, is the etiologic infectious agent of this disease. Objective.—The significantly higher incidence of progressive multifocal leukoencephalopathy in patients with acquired immunodeficiency syndrome than in patients with other immunosuppressive conditions suggests that molecular interactions between human immunodeficiency virus 1 and JCV, via the Tat protein, are responsible for the activation of the JCV enhancer/promoter and the development of progressive multifocal leukoencephalopathy. An indirect mechanism through activation of cytokines, such as transforming growth factor β1 and Smads 3 and 4, may also be responsible for the enhancement of JCV gene expression. Design.—Immunohistochemical analysis in progressive multifocal leukoencephalopathy samples and chloramphenicol acetyl transferase assays on cell cultures were performed to corroborate this hypothesis. Results.—The JCV capsid protein VP-1 was found in the nuclei of oligodendrocytes and in the nuclei and cytoplasm of bizarre astrocytes. Human immunodeficiency virus proteins, including p24 and Tat, were detected in the cytoplasm of astrocytes. Tat, but not p24, was detected in oligodendrocytes, suggesting that extracellular Tat accumulates in the nuclei of oligodendrocytes, where JCV gene transcription takes place. High levels of transforming growth factor β1 and Smads 3 and 4 were detected in JCV-infected oligodendrocytes. Results from in vitro studies confirm activation of the JCV early and late promoters by Smads 3 and 4. Conclusions.—These observations support our model, suggesting that the induction of transforming growth factor β1 by human immunodeficiency virus 1 Tat can stimulate its downstream factors, including Smads 3 and 4, which in turn augment transcription of the JCV promoter in glial cells.

scholarly journals Progressive multifocal leukoencephalopathy in human immunodeficiency virus type 1-infected patients: absence of correlation between JC virus neurovirulence and polymorphisms in the transcriptional control region and the major capsid protein loci

2001 ◽  
Vol 82 (4) ◽  
pp. 899-907 ◽  
Author(s):  
Monica Sala ◽  
Jean-Pierre Vartanian ◽  
Pascale Kousignian ◽  
Jean-François Delfraissy ◽  
Yassine Taoufik ◽  
...  
Keyword(s):  
Progressive Multifocal Leukoencephalopathy ◽  
Capsid Protein ◽  
Control Region ◽  
Transcriptional Control ◽  
Major Capsid Protein ◽  
Demyelinating Disease ◽  
Jc Virus ◽  
Capsid Protein Gene ◽  
Transcriptional Control Region ◽  
Genomic Marker

Progressive multifocal leukoencephalopathy (PML) is a rapidly fatal demyelinating disease of the central nervous system related to JC polyomavirus (JCV) replication in oligodendrocytes. PML usually occurs in immunocompromised individuals, especially in the setting of AIDS. Administration of highly active anti-retroviral therapy (HAART) may improve survival prognosis in some, but not all, patients with AIDS-related PML. This observation might be explained by the outgrowth of some JCV variants of increased fitness. To evaluate this hypothesis, two subgroups of five patients with AIDS-related PML, started on HAART after PML diagnosis, were analysed. The non-responder (NR) patients died rapidly despite HAART, while responders (R) had a positive outcome and were still alive. JCV DNA was extracted from cerebrospinal fluid biopsies and two regions of the genome were analysed, the transcriptional control region (TCR) and the major capsid protein gene (VP1). Both regions show different degrees of polymorphism and are recognized as evolving independently. Sequence analysis demonstrated that (i) extensive TCR rearrangements were present in both subgroups of patients, (ii) VP1 sequence polymorphisms could be identified in the BC loop, suggesting the absence of immune selection, and (iii) no genomic marker for JCV specific neurovirulence could be identified in the TCR and VP1 loci.

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