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PubMed2005

Therapeutic targeting of alpha 4-integrins in chronic inflammatory diseases: tipping the scales of risk towards benefit?

Inhibition of leukocyte trafficking via alpha4-integrin antibody blockade has recently become a validated therapeutic approach for several inflammatory diseases, including multiple sclerosis, ulcerative colitis and Crohn's disease. In the midst of this recent success, 3 patients receiving chronic treatment with the anti-alpha4 antagonist natalizumab (Tysabri) for the treatment of multiple sclerosis or Crohn's disease, developed JC-virus related progressive multifocal leukoencephalopathy (PML). These unforeseen consequences suggest that long term blockade of alpha4-integrins might prevent trafficking of non-pathogenic lymphocytes that are essential for viral immunosurveillance. In the current issue of the European Journal of Immunology Bjursten and colleagues report that long term treatment with anti-alpha4-integrin antibodies results in exacerbation of the murine model of colitis induced by the targeted deletion of the heterotrimeric G protein subunit Galphai2. In order to properly evaluate the efficacy and safety of anti-alpha4-integrin therapy, the relationship between these observations in an immunologically altered animal model and human clinical disease needs to be carefully measured.

Animals↗

PubMed2005

The agnoprotein of polyomaviruses: a multifunctional auxiliary protein.

The late region of the three primate polyomaviruses (JCV, BKV, and SV40) encodes a small, highly basic protein known as agnoprotein. While much attention during the last two decades has focused on the transforming proteins encoded by the early region (small and large T-antigens), it has become increasingly evident that agnoprotein has a critical role in the regulation of viral gene expression and replication, and in the modulation of certain important host cell functions including cell cycle progression and DNA repair. The importance of agnoprotein is underscored by its expression during lytic infection of glial cells by JCV that occurs in progressive multifocal leukoencephalopathy (PML), and also in some JCV-associated human neural tumors particularly medulloblastoma. In this review, we will discuss the structure and function of agnoprotein in the viral life cycle during the course of lytic infection and the consequences of agnoprotein expression for the host cell.

Amino Acid Sequence↗

PubMed1999

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

The human polyomavirus JCV lytically infects oligodendrocytes of immunosuppressed individuals leading to the fatal demyelinating disease termed progressive multifocal leukoencephalopathy (PML). Dementia, hemiparesis, and hemianopsia are the predominant presenting signs of PML. Asymptomatic JCV infection is common worldwide with approximately 80% of adults testing positive for JCV antibodies. In addition to the brain, JCV has been shown to infect tonsil, lymphoid, bone marrow, and kidney tissues. Viral variants, classified according to the nucleotide sequences of their regulatory regions, are being mapped in human tissues and cell types to help trace the pathway of JCV from a site of initial infection to target oligodendrocytes. In most literature, a dichotomy of the JCV regulatory region structure exists by tissue. B lymphocytes, however, have demonstrated the capacity to harbor JCV of diverse regulatory regions, which helps position their interaction with virus amid every stage of infection and implicates a lymphocytic role in latency.

Animals↗

PubMed1994

Propagation of JC virus in human neuroblastoma cell line IMR-32.

JC virus (JCV), the causative agent of a human demyelinating disease, progressive multifocal leukoencephalopathy, has a very narrow host range. Cells permissive for infection by JCV have been essentially limited to primary human fetal glial cells, which are difficult to obtain and maintain. In pilot studies, it was found that JCV can multiply in an established cell line of human neuroblastoma. JCV strains Mad-1 and Tokyo-1 were inoculated, respectively, into two cell lines, IMR-32 (neuroblastoma) and A-172 (glioblastoma). Viral infection with cytopathic effect was observed only in IMR-32 cells, and the most efficient viral proliferation was obtained in cells cultured in medium containing 2% fetal calf serum (FCS). Both Mad-1 and Tokyo-1 strains propagated well, with the former being more efficient than the latter. Viral replication was confirmed by immunofluorescence, electron microscopy, and a hemagglutination assay. Sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis and Western blot analysis of the purified virus revealed the characteristic JCV protein profile. Thus, IMR-32 cells have been found to be permissive for JCV, which should provide a useful system for further studies of virus proliferation and viral tissue tropism.

Blotting, Western↗

PubMed2004

Simultaneous detection and differentiation of human polyomaviruses JC and BK by a rapid and sensitive PCR-ELAHA assay and a survey of the JCV subtypes within an Australian population.

Human polyomaviruses JCV and BKV can cause several clinical manifestations in immunocompromised hosts, including progressive multifocal leukoencephalopathy (PML) and haemorrhagic cystitis. Molecular detection by polymerase chain reaction (PCR) is recognised as a sensitive and specific method for detecting human polyomaviruses in clinical samples. In this study, we developed a PCR assay using a single primer pair to amplify a segment of the VP1 gene of JCV and BKV. An enzyme linked amplicon hybridisation assay (ELAHA) using species-specific biotinylated oligonucleotide probes was used to differentiate between JCV and BKV. This assay (VP1-PCR-ELAHA) was evaluated and compared to a PCR assay targeting the human polyomavirus T antigen gene (pol-PCR). DNA sequencing was used to confirm the polyomavirus species identified by the VP1-PCR-ELAHA and to determine the subtype of each JCV isolate. A total of 297 urine specimens were tested and human polyomavirus was detected in 105 specimens (35.4%) by both PCR assays. The differentiation of JCV and BKV by the VP1-PCR-ELAHA showed good agreement with the results of DNA sequencing. Further, DNA sequencing of the JCV positive specimens showed the most prevalent JCV subtype in our cohort was 2a (27%) followed by 1b (20%), 1a (15%), 2c (14%), 4 (14%) and 2b (10%). The results of this study show that the VP1-PCR-ELAHA is a sensitive, specific and rapid method for detecting and differentiating human polyomaviruses JC and BK and is highly suitable for routine use in the clinical laboratory.

Adolescent↗

PubMed2001

Neurological and developmental effects of HIV and AIDS in children and adolescents.

HIV-related encephalopathy is an important problem in vertically infected children with HIV. Infected infants may manifest early, catastrophic encephalopathy, with loss of brain growth, motor abnormalities, and cognitive dysfunction. Even without evidence of AIDS, infected infants score lower than serorevertors on developmental measures, particularly language acquisition. Children with perinatal or later transfusion-related infection generally are roughly comparable developmentally to their peers until late in their course. Symptoms similar to adult AIDS dementia complex are occasionally seen in adolescents with advanced AIDS, including dementia, bradykinesia, and spasticity. Opportunistic CNS infections such as toxoplasmosis and progressive multifocal leukoencephalopathy are less common in children and adolescents than in adults. Increasing evidence suggests that aggressive antiretroviral treatment may halt or even reverse encephalopathy. Neuroimaging changes may precede or follow clinical manifestations, and include early lenticulostriate vessel echogenicity on cranial ultrasound, calcifying microangiopathy on CT scan, and/or white matter lesions and central atrophy on MRI. Differential diagnosis of neurological dysfunction in an HIV-infected infant includes the effects of maternal substance abuse, other CNS congenital infections, and other causes of early static encephalopathy. Initial entry of HIV into the nervous system occurs very early in infection. The risk of clinical HIV encephalopathy increases with very early age of infection and with high viral loads. Virus is found in microglia and brain derived macrophages, not neurons. The neuronal effect of HIV is probably indirect, with various cytokines implicated. Apoptosis is the presumed mechanism of damage to neurons by HIV.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Viral proteomics: a promising approach for understanding JC virus tropism.

The human polyomavirus JC virus (JCV) is responsible for the CNS demyelination observed in cases of progressive multifocal leukoencephalopathy. The JCV regulatory region (promoter) is a hypervariable, noncoding, nucleotide sequence positioned between the early and late protein-coding regions in the viral genome. Selective binding of cellular transcription factors to this promoter region participates in the control of viral tropism. Hence, further study of these proteins might provide new insights into JCV tropism and associated pathogenesis. This review gives an overview of viral proteomics - the study of all proteins expressed from the viral gene transcripts, and all the cellular proteins that play a role in JCV tropism. It also describes a new biochemical approach for studying relevant JCV promoter-binding proteins, which is an anchored-JCV transcriptional promoter (ATP) assay. An ATP assay utilizes the product of PCR-amplified JCV promoter sequences coupled with Sepharose beads in order to capture and isolate cellular nuclear proteins with specific promoter-binding affinity for analysis. Proteins that bind to JCV-ATPs can be eluted and subjected to proteomic analysis. Insights from this approach may improve the understanding of viral and cellular parameters that control JCV tropism.

Deoxyribonuclease I↗

PubMed1993

Inhibition of human neurotropic virus (JCV) DNA replication in glial cells by camptothecin.

Progressive multifocal leukoencephalopathy is a subacute demyelinating disease of the central nervous system (CNS) resulting from opportunistic infections in immunocompromised patients infected with a common polyomavirus, JC virus (JCV). Unlike other polyomaviruses, JCV exhibits an unusually narrow tissue tropism by primarily infecting glial cells of the CNS. JCV DNA replication is similar to that of the well-characterized papovavirus, SV40, which requires the viral early protein T-antigen and host-replication factors including DNA polymerases and DNA topoisomerase I. In this study we have been able to effectively block replication of viral DNA in glial cells using camptothecin, a drug which inhibits DNA topoisomerase activity. Pulse-treatment of cells with non-toxic levels of camptothecin specifically blocks viral DNA replication with no inhibitory effect on host transcription and translation processes as examined by viral gene expression in the transfected cells. Furthermore, drug treatment of the cells exhibits no significant effect on DNA topoisomerase I gene transcription. We further demonstrate that repeated pulse-treatment of cells with the drug is required for complete blockage of viral DNA replication. The importance of these findings in the treatment of AIDS encephalopathy is discussed.

Antineoplastic Agents↗

PubMed1994

A 70- to 80-kDa glial cell protein interacts with the AGGGAAGGGA domain of the JC virus early promoter only in the presence of the neighboring cis DNA elements.

The neurotropic virus JC (JCV) causes the demyelinating disease progressive multifocal leukoencephalopathy. JCV is transcriptionally regulated by both positive and negative cis elements. Previous studies have shown that the AGGGAAGGGA sequence, in isolation, interacts with a 53- to 56-kDa cellular protein and acts as a silencer for the late promoter. We have reexamined the role of the AGGGAAGGGA element in the glial cell-specific transcriptional regulation of JCV by studying it in a longer natural context of elements of the JCV early promoter. Transcriptional analysis in C6 glial cells of selectively mutated AGGGAAGGGA domains within the nt 98-153 region of the JCV early promoter revealed that both GGG regions in the AGGGAAGGGA sequence are required for glial cell-specific transcription. The interactions of cellular proteins with the AGGGAAGGGA domain were also found to be dependent upon the presence or absence of neighboring cis elements. The TATA region was found to facilitate the interaction of specific proteins with the AGGGAAGGGA domain. Domain-specific photocrosslinking studies revealed the binding of a glial cell protein of approximately 70-80 kDa to the AGGGAAAGGGA domain only when it was flanked by its neighboring cis elements, the TATA and NF-1 domains of the JCV promoter.

Affinity Labels↗

PubMed1994

DNA replication of chimeric JC virus-simian virus 40 genomes.

The ubiquitous virus JCV is the etiologic agent of the human brain disease progressive multifocal leukoencephalopathy. Although infection usually occurs early in life and the virus can remain latent in human tissues, including brain, little information is available regarding its replication. It is known that DNA replication of primate polyomaviruses is dependent upon the synthesis of T antigen and the subsequent interactions of this protein with cellular factors and the viral origin of replication. We constructed chimeric genomes between JCV and SV40, two genetically similar viruses with distinct biologies, in which segments of the T antigen coding region and the replication origin were exchanged. Because the engineering of these genomes created a defect in the structural protein VP1, their DNA replicating activities could be compared without the complication of secondary infection of adjacent cells and amplification of the replication signal. The ability of the JCV-SV40 hybrid T antigens to initiate replication from the two viral origins in primate cells was investigated. A region of the JCV T antigen that includes the DNA binding and zinc finger domains was found to be responsible for the failure of JCV T antigen to interact productively with the SV40 origin. In addition, the ability to replicate in monkey cells was limited to constructs expressing T antigens which contained the carboxy-terminal host range domain of SV40.

Antigens, Polyomavirus Transforming↗

PubMed1996

Sequences within the early and late promoters of archetype JC virus restrict viral DNA replication and infectivity.

Two forms of JC virus (JCV) have been isolated from its human host, an archetype found in kidney tissue and urine of nonimmunocompromised individuals and a rearranged type detected in lymphocytes and brain tissue of patients with and without progressive multifocal leukoencephalopathy. To investigate the hypothesis that alterations to the archetype transcriptional control region yield rearranged forms of the virus exhibiting new tissue tropic and pathogenic potentials, attempts were made to propagate archetype JCV in human renal and glial cell cultures. Although rearranged forms of JCV multiplied in these cells, archetype JCV failed to do so. Through the use of chimeric and mutant viral genomes, and a cell line that constitutively expresses viral T protein, we demonstrated that archetype's inactivity relative to that of rearranged forms was due to differences in the promoter-enhancer and not in the protein coding regions or origin of DNA replication. Additional analyses revealed that the absence of a large tandem duplication and the presence of a 23- and a 66-base pair sequence in the archetype transcriptional control region were responsible for this restricted lytic behavior. We discuss the possibility that deletion and duplication events within the archetype promoter-enhancer might yield more active viral variants via the loss of a negative, or the creation of a positive, transcriptional control signal(s).

Adult↗

PubMed1996

Purified JC virus T antigen derived from insect cells preferentially interacts with binding site II of the viral core origin under replication conditions.

The human polyomavirus JC virus (JCV) establishes persistent, asymptomatic infections in most individuals, but in severely immunocompromised hosts it may cause the fatal demyelinating brain disease progressive multifocal leukoencephalopathy. In cell culture JCV multiplies inefficiently and exhibits a narrow host range. This restricted behavior occurs, in part, at the level of DNA replication, which is regulated by JCV's multifunctional large tumor protein (TAg). To prepare purified JCV TAg (JCT) for biochemical analyses, the recombinant baculovirus B-JCT was generated by cotransfection of insect cells with wild-type baculovirus and the vector pVL-JCT(Int-) containing the JCT-coding sequence downstream of the efficient polyhedrin promoter. JCT expressed in infected cells was immunoaffinity purified using the anti-JCT monoclonal antibody PAb 2000. Characterization of the viral oncoprotein indicated that it exists in solution as a mixture of monomeric and oligomeric species. With the addition of ATP, the population of monomers decreased and that of hexamers and double hexamers increased. A DNA mobility shift assay indicated that origin binding occurred primarily with the double-hexamer form. A comparison of the specific DNA-binding activities of JCT and SV40 TAg (SVT) revealed that JCT generally exhibited greater affinity for binding site II relative to binding site I (B.S. I) of both viral origin regions, whereas SVT preferentially bound B.S. I. Furthermore, JCT bound nonviral DNA more efficiently than did SVT. These functional differences between the two TAgs may contribute to the reduced DNA replication potential of JCV in vitro, and to the virus' ability to establish persistent infections in vivo.

Animals↗

PubMed1996

Evidence that the soluble factors secreted by activated immune cells suppress replication of human neurotropic JC virus DNA in glial cells.

Coordination of the immune response to viral infection and disease in the brain is believed to involve bidirectional interaction between the immune system and the central nervous system (CNS). Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the CNS that generally affects patients exhibiting an immunocompromised condition due to various illnesses. The human polyomavirus, JCV, which infects greater than 70% of the adult population is the etiological agent of this disease. Infection with JCV occurs during childhood and the virus remains in the latent state with no apparent clinical signals. However, under immunocompromised conditions, the virus enters the lytic cycle, and upon cytolytic destruction of glial cells, causes PML. To understand the molecular mechanism underlying immune regulation of JCV replication, we have developed a cell culture system and have investigated the effect of soluble factors from T-cell cultures on replication of JCV DNA in glial cells. Our data demonstrate that replication of JCV DNA in the presence of PMA-stimulated T-cell supernatant is substantially decreased in transfected glial cells. Heat-inactivation and size-fractionation studies revealed participation of a heat labile factor(s) which loses its maximum activity at 60 degrees and ranges between 30 and 100 kDa in size. The unfractionated T-cell supernatant and the fraction enriched in 30- to 100-kDa proteins reduced the level of viral DNA replication during the early phase of the lytic cycle. These observations suggest that regulatory factors which are secreted by immune cells may modulate the level of JCV DNA replication in glial cells. The importance of these observations in reactivation of JCV in immunocompromised individuals and development of PML is discussed.

Antigens, Polyomavirus Transforming↗

PubMed1997

Screening human tumor samples with a broad-spectrum polymerase chain reaction method for the detection of polyomaviruses.

Polyomaviruses induce tumors of different histological types when inoculated into experimental animals. An etiological role for this virus group in the development of malignant tumors in humans remains questionable, despite several reports demonstrating the presence of SV40, JCV, and BKV DNA in human cancers. Only two human polyomavirus types are known to date: JCV, causing progressive multifocal leukoencephalopathy (PML) under severe immunosuppression, and BKV, first isolated from the urine of a renal transplant recipient and associated with hemorrhagic cystitis. We developed a degenerate polymerase chain reaction assay in an attempt to identify additional, presently unknown human polyomavirus types that may be involved in the malignant transformation of human tissues. A large part of the gene coding for the viral capsid protein VP1 is highly conserved in nine polyomavirus types (and their strains) and was therefore selected as most suitable for the primer design. Degenerate oligonucleotide primers were deduced from four different conserved amino acid motifs in this region. Three different sets of primers were included in each test to obtain the highest sensitivity in combination with primers with the lowest degeneracy numbers. The sensitivity obtained ranged from 1 copy/cell for bovine polyomavirus to 100 copies/cell for LPV after ethidium bromide staining and was increased at least 10-fold after hybridization with a radiolabeled probe. A subsequent seminested amplification allowed for the detection of 1 copy/cell for LPV. These degenerate primers were applied to analyze bladder carcinomas, Hodgkin lymphomas, meningiomas, Kaposi tumors, and Kaposi-derived cell lines. No polyomavirus DNA sequences could be detected.

Animals↗

PubMed2000

Human cytomegalovirus immediate-early gene 2 expression leads to JCV replication in nonpermissive cells via transcriptional activation of JCV T antigen.

Human papovavirus JCV is the causative agent of the demyelinating brain disease progressive multifocal leukoencephalopathy (PML) that typically develops as a complication of impaired immunocompetence. JCV displays a strong tropism for glial cells which is correlated by glial-specific transcriptional regulation of viral gene expression. In a previous report HCMV was shown to overcome the restricted cell specificity of JCV by inducing DNA replication of a PML-derived JCV strain in human fibroblasts which are nonpermissive for the replication of JCV alone. Here we show that productive JCV replication is induced by HCMV in human glioblastoma cells. Both in fibroblasts and in glioblastoma cells, the HCMV immediate-early transactivator 2 (IE2) is sufficient to mediate JCV replication. Furthermore, IE2 induces DNA replication of several structurally different brain- or kidney-derived JCV variants. IE2-induced JCV DNA replication is accompanied by the induction of JCV T antigen expression due to stimulation of the JCV early promoter. Our results indicate that stimulation of JCV early gene expression by HCMV-IE2 is sufficient to overcome the restricted cell specificity of JCV.

Antigens, Polyomavirus Transforming↗

PubMed2002

Construction of a novel JCV/SV40 hybrid virus (JCSV) reveals a role for the JCV capsid in viral tropism.

JC virus (JCV) is a common human polyomavirus that infects greater than 70% of the general population worldwide. JCV is also the causative agent of progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease of the CNS. Currently, little is known about the mechanisms that restrict JCV tropism to a few human cell types and tissues. In vivo, JCV can be detected in oligodendrocytes and astrocytes in the CNS of patients with PML. The virus can also be detected in kidney, tonsil, and B lymphocytes of patients both with and without PML. In vitro, JCV can only be propagated in cultures of human fetal glial cells or in cell lines derived from this tissue. In contrast, the closely related monkey polyomavirus, SV40, has a broad tropism for primate cells, including those cells that are also susceptible to infection by JCV. We hypothesized that one potential block to infection is at the level of virus entry. To examine this, we constructed a JCV-SV40 chimeric viral genome that contains the regulatory region and the early genes of SV40 and the late structural genes of JCV. The hybrid virus (JCSV) induced SV40-like cytopathic effect in human glial cells and hemagglutinated human type O red blood cells similar to JCV. More importantly, the hybrid virus maintained the host range of JCV, suggesting that interactions between the virus capsid and host cell receptors contribute to JCV tropism.

Animals↗

PubMed2006

Polyomaviruses and human diseases.

Polyomaviruses are small, nonenveloped DNA viruses, which are widespread in nature. In immunocompetent hosts, the viruses remain latent after primary infection. With few exceptions, illnesses associated with these viruses occur in times of immune compromise, especially in conditions that bring about T cell deficiency. The human polyomaviruses BKV and JCV are known to cause, respectively, hemorrhagic cystitis in recipients of bone marrow transplantation and progressive multifocal leukoencephalopathy in immunocompromised patients, for example, by HIV infection. Recently, transplant nephropathy due to BKV infection has been increasingly recognized as the cause for renal allograft failure. Quantitation of polyomavirus DNA in the blood, cerebrospinal fluid, and urine, identification of virus laden "decoy cells" in urine, and histopathologic demonstration of viral inclusions in the brain parenchyma and renal tubules are the applicable diagnostic methods. Genomic sequences of polyomaviruses have been reported to be associated with various neoplastic disorders and autoimmune conditions. While various antiviral agents have been tried to treat polyomavirus-related illnesses, current management aims at the modification and/or improvement in the hosts' immune status. In this chapter, we provide an overview of polyomaviruses and briefly introduce its association with human diseases, which will be covered extensively in other chapters by experts in the field.

Antiviral Agents↗

PubMed2006

Pharmacotherapeutic options for the management of human polyomaviruses.

Polyomaviruses [BK virus (BKV), JC virus (JCV) and simian virus 40 (SV40)] have been known to be associated with diseases in humans for over thirty years. BKV-associated nephropathy and JCV-induced progressive multifocal leukoencephalopathy (PML) were for many years rare diseases occurring only in patients with underlying severe impaired immunity. Over the past decade, the use of more potent immunosuppression (IS) in transplantation, and the Acquired Immune Deficiency Syndrome (AIDS) epidemic, have coincided with a significant increase in the prevalence of these viral complications. Prophylactic and therapeutic interventions for human polyomavirus diseases are limited by our current understanding of polyomaviral pathogenesis. Clinical trials are limited by small numbers of patients affected with clinically significant diseases, lack of defined risk factors and disease definitions, no proven effective treatment and the overall significant morbidity and mortality associated with these diseases. This chapter will focus on a review of the current and future research related to therapeutic targets and interventions for polyomavirus-associated diseases.

Disease Management↗