Molecular Regulation of JC Virus Tropism: Insights into Potential Therapeutic Targets for Progressive Multifocal Leukoencephalopathy

Marshall, Leslie J.; Major, Eugene O.

doi:10.1007/s11481-010-9203-1

Cited by 60 publications

(57 citation statements)

References 191 publications

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“…Much less frequently, the rearranged form of JCV can be found in the urine of patients experiencing asymptomatic reactivation 13 . In addition to RR, variability in VP1 sequences found in CSF and brain of PML patients, but not in urine, also reinforces the relationship between the variants or genetic changes and viral tropism 14,15 . Currently, the most accepted idea is that PML arises as a consequence of reactivation of latent JCV in the kidneys, leading to viremia and as a consequence, viruses present in blood and/or B-lymphocytes enter the brain and cause disease.…”

Section: A Short Background Of Pmlmentioning

confidence: 59%

Natalizumab treatment for multiple sclerosis: updates and considerations for safer treatment in JCV positive patients

Nali

Moraes

Fink

et al. 2014

Arq. Neuro-Psiquiatr.

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Natalizumab is currently one of the best options for treatment of patients with Multiple Sclerosis who have failed traditional prior therapies. However, prolonged use, prior immunosuppressive therapy and anti-JCV antibody status have been associated with increased risk of developing progressive multifocal leukoencephalopathy (PML). The evaluation of these conditions has been used to estimate risks of PML in these patients, and distinct (sometimes extreme) approaches are used to avoid the PML onset. At this time, the biggest issue facing the use of Natalizumab is how to get a balance between the risks and the benefits of the treatment. Hence, strategies for monitor JCV-positive patients undergoing Natalizumab treatment are deeply necessary. To illustrate it, we monitored JCV/DNA in blood and urine of a patient receiving Natalizumab for 12 months. We also bring to discussion the effectiveness of the current methods used for risk evaluation, and the real implications of viral reactivation.Keywords: multiple sclerosis, Natalizumab, JCV, risk factors, progressive multifocal leucoencephalopaty, viruria. RESUMO Natalizumabe é atualmente uma das melhores opções para o tratamento de pacientes com Esclerose Múltipla que não respondem aos tratamentos tradicionais. No entanto, o seu uso prolongado, o uso de terapia imunossupressora prévia e o status sorológico antivírus JC têm sido associados com o risco aumentado de desenvolvimento de Leucoencefalopatia Multifocal Progressiva (LEMP). A avaliação destas condições tem sido utilizada para estimar os riscos do desenvolvimento de LEMP nestes pacientes, e abordagens distintas (por vezes extremas) são empregadas para evitar o aparecimento dessa patologia. Atualmente, o grande desafio está em obter um equilíbrio entre os riscos e os benefícios do tratamento com Natalizumabe. Assim, é crucial desenvolver estratégias para monitorar pacientes portadores do vírus JC sob tratamento com Natalizumabe. A título de ilustração, pesquisamos o vírus no sangue e na urina de um paciente sob tratamento durante 12 meses. Também discutimos a eficácia dos métodos atualmente utilizados para avaliação de riscos e as implicações reais de reativação viral.Palavras-chave: esclerose múltipla, Natalizumabe, vírus JC, leucoencefalopatia multifocal progressiva, viruria. Natalizumab (Tysabri), used for treatment of relapsingremitting multiple sclerosis (MS), is a monoclonal antibody directed to the a4b1 integrin, a subunit of an adhesion molecule expressed on the surface of T lymphocytes. The antibodies act by blocking the migration of T Lymphocytes from blood to the CNS through the blood brain barrier (BBB) and attenuate the inflammatory effects 1 . The AFFIRM study showed that monotherapy with Natalizumab (NTZ) for 2 years decreased the relapse rate by 68% and the disability progression rate by 42% compared with placebo 2 . NTZ is well tolerated and the overall incidence of serious adverse events is low. Although the efficacy of NTZ is up to

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Section: A Short Background Of Pmlmentioning

confidence: 59%

Natalizumab treatment for multiple sclerosis: updates and considerations for safer treatment in JCV positive patients

Nali

Moraes

Fink

et al. 2014

Arq. Neuro-Psiquiatr.

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“…Interestingly, the related JCPyV NCCR also bears an SP1-4-like site in the D block close to the LVGR that is frequently lost in natural NCCR rearrangements in patients with progressive multifocal leukoencephalopathy (18,44,45). Other TFBS proposed to contribute to JCPyV EVGR activation include Spi-B, which is a member of the Ets family (46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

Sp1 Sites in the Noncoding Control Region of BK Polyomavirus Are Key Regulators of Bidirectional Viral Early and Late Gene Expression

Bethge

Hachemi

Manzetti

et al. 2015

J Virol

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In kidney transplant patients with BK polyomavirus (BKPyV) nephropathy, viral variants arise bearing rearranged noncoding control regions (rr-NCCRs) that increase viral early gene expression, replicative fitness, and cytopathology. rr-NCCRs result from various deletions and duplications of archetype NCCR (ww-NCCR) sequences, which alter transcription factor binding sites (TFBS). However, the role of specific TFBS is unclear. We inactivated 28 TFBS in the archetype NCCR by selective point mutations and examined viral gene expression in bidirectional reporter constructs. Compared to the archetype, group 1 mutations increased viral early gene expression similar to rr-NCCR and resulted from inactivating one Sp1 or one Ets1 TFBS near the late transcription start site (TSS). Group 2 mutations conferred intermediate early gene activation and affected NF1, YY1, and p53 sites between early and late TSS. BK polyomavirus (BKPyV) is one of now more than 12 human PyVs (1) and is known to infect more than 90% of the human population during early childhood (2-6). Following primary infection, BKPyV persists latently in the renourinary tract, with intermittent periods of asymptomatic shedding into urine (5, 7). BKPyV disease typically occurs in individuals with altered immune functions, to which viral determinants are thought to contribute (3, 8). Thus, BKPyV causes nephropathy in 1 to 14% of kidney transplant patients and hemorrhagic cystitis in 5 to 20% of allogeneic hematopoietic stem cell transplant recipients (2, 9).BKPyV strains excreted in urine of healthy immunocompetent individuals typically bear a noncoding control region (NCCR) of linear archetype (ww) architecture (ww-NCCR) (5, 10, 11) and grow slowly in primary human urothelial and renal tubular epithelial cells (8,12). In immunosuppressed kidney transplant patients with early stages of BKPyV-associated nephropathy, the virus contains mostly archetype ww-NCCR (8, 13). However, when immunosuppression is not readily reduced to permit specific T cells to resume control over BKPyV replication (14-17), viral variants with rearranged NCCRs (rr-NCCRs) emerge that are associated with higher plasma viral loads and more severe renal allograft pathology (8). Similar rr-NCCRs of JC polyomavirus have been linked with the emergence of progressive multifocal leukoencephalopathy, a debilitating, often fatal brain disease in immunocompromised patients with HIV/AIDS or receiving transplantation or therapies for cancer and immune diseases (18)(19)(20)(21)(22). The archetype NCCR of polyomaviruses is approximately 400 bp in length and harbors the origin of replication as well as bidirectional promoter/ enhancer functions that, in concert with the host cell signals, control the timing and sequential activation of early viral gene region (EVGR) expression, viral DNA genome replication, and late viral gene region (LVGR) expression. Notably, EVGR and LVGR are encoded and transcribed in opposite directions from the NCCR (23). The ϳ2.3-kb EVGR encodes the small T antigen, the large ...

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“…Özellikle lenforetiküler dokularda, böbrek ve beyinde latent olarak bulunur ve immünsüpresyon ile reaktivasyon durumunda PML'ye neden olur. [3][4][5][6] PML en çok oksipital ve frontal serebral beyaz cevheri etkiler. Serebellar ve beyin sapı tutulumu bu lokalizasyonları takip eder.…”

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“…Ancak PML için kanıtlanmış etkili bir tedavi henüz yoktur ve prognoz genelde fataldir. [3][4][5][6] OLGU SUNUMU Yetmiş iki yaşında kadın hastanın kliniğimize baş-vurusundan 15 gün önce aniden konuşma bozukluğu başlamış ve dört gün önce de sağ taraflı güçsüzlüğü ile yürümede dengesizliği eklenmiş. Şi-kâyetleri progresif seyretmekteymiş.…”

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“…Özellikle virüsün reaktivasyonu ile PML tablosunun ortaya çıktığı hematolojik malignansiler, AIDS ve monoklonal antikor tedavilerindeki sıklığı ile latent olarak seçtiği dokular, hastalık patogenezinin anlaşılması ve yeni tedavi hedefleri açısından yol gösterici olacaktır. 4,5 İmmünsüpresyonu olan bir hastada özellikle hücre aracılı bir immün defekt varsa, subakut progresif fokal nörolojik bir tablo gelişiyorsa PML mutlaka araştırılmalıdır. Fokal nörolojik sendromun serebrovasküler olayı taklit edecek şekilde hastamızda olduğu gibi akut başlayabileceği akılda bulundurulmalıdır.…”

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Progressive Multifocal Leukoencephalopathy in Chronic Lymphocytic Leukemia: Case Report and Review of the Literature

Eker¹,

Serakıncı²,

Süer³

et al. 2015

Turkiye Klinikleri J Case Rep

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Molecular Regulation of JC Virus Tropism: Insights into Potential Therapeutic Targets for Progressive Multifocal Leukoencephalopathy

Cited by 60 publications

References 191 publications

Natalizumab treatment for multiple sclerosis: updates and considerations for safer treatment in JCV positive patients

Natalizumab treatment for multiple sclerosis: updates and considerations for safer treatment in JCV positive patients

Sp1 Sites in the Noncoding Control Region of BK Polyomavirus Are Key Regulators of Bidirectional Viral Early and Late Gene Expression

Progressive Multifocal Leukoencephalopathy in Chronic Lymphocytic Leukemia: Case Report and Review of the Literature

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