JC Virus Latency in the Brain and Extraneural Organs of Patients with and without Progressive Multifocal Leukoencephalopathy

Tan, Chen; Ellis, Laura; Wüthrich, Christian; Ngo, Long; Broge, Thomas; Saint-Aubyn, Jenny; Miller, Joel; Koralnik, Igor J.

doi:10.1128/jvi.00609-10

Cited by 106 publications

(86 citation statements)

References 31 publications

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“…Following duplication of the early promoter and deletion of the late promoter sequences, the JCPyV rr-NCCRs demonstrate activation of EVGR at the expense of LVGR similar to those of BKPyV (46). These alterations also broaden the host cell range, which has particular relevance for neurotropism and pathology (34,63,64). Given the power of the bidirectional reporter construct to predict PyV NCCR expression and viral replication, our approach may help to close the current knowledge gaps in viral host cell specificity and replication of the dozen novel human PyVs.…”

Section: Discussionmentioning

confidence: 99%

Imperfect Symmetry of Sp1 and Core Promoter Sequences Regulates Early and Late Virus Gene Expression of the Bidirectional BK Polyomavirus Noncoding Control Region

Bethge

Ajuh

Hirsch

2016

J Virol

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Rearrangements or point mutations in the noncoding control region (NCCR) of BK polyomavirus (BKPyV) have been associated with higher viral loads and more pronounced organ pathology in immunocompromised patients. The respective alterations affect a multitude of transcription factor binding sites (TFBS) but consistently cause increased expression of the early viral gene region (EVGR) at the expense of late viral gene region (LVGR) expression. By mutating TFBS, we identified three phenotypic groups leading to strong, intermediate, or impaired EVGR expression and corresponding BKPyV replication. Unexpectedly, Sp1 TFBS mutants either activated or inhibited EVGR expression when located proximal to the LVGR (sp1-4) or the EVGR (sp1-2), respectively. We now demonstrate that the bidirectional balance of EVGR and LVGR expression is dependent on affinity, strand orientation, and the number of Sp1 sites. Swapping the LVGR-proximal high-affinity SP1-4 with the EVGR-proximal low-affinity SP1-2 in site strand flipping or inserting an additional SP1-2 site caused a rearranged NCCR phenotype of increased EVGR expression and faster BKPyV replication. The 5= rapid amplification of cDNA ends revealed an imperfect symmetry between the EVGR-and LVGR-proximal parts of the NCCR, consisting of TATA and TATA-like elements, initiator elements, and downstream promoter elements. Mutation or deletion of the archetypal LVGR promoter, which is found in activated NCCR variants, abrogated LVGR expression, which could be restored by providing large T antigen (LTag) in trans. Thus, whereas Sp1 sites control the initial EVGR-LVGR expression balance, LTag expression can override inactivation of the LVGR promoter and acts as a key driver of LVGR expression independently of the Sp1 sites and core promoter elements. IMPORTANCEPolyomaviridae currently comprise more than 70 members, including 13 human polyomaviruses (PyVs), all of which share a bidirectional genome organization mediated by the NCCR, which determines species and host cell specificity, persistence, replication, and virulence. Here, we demonstrate that the BKPyV NCCR is fine-tuned by an imperfect symmetry of core promoter elements centered around TATA and TATA-like sequences close to the EVGR and LVGR, respectively, which are governed by the directionality and affinity of two Sp1 sites. The data indicated that the BKPyV NCCR is poised toward EVGR expression, which can be readily unlatched by a simple switch affecting Sp1 binding. The resulting LTag, which is the major EVGR protein, drives viral genome replication, renders subsequent LVGR expression independently of archetypal promoter elements, and can overcome enhancer/promoter mutations and deletions. The data are pivotal for understanding how human PyV NCCRs mediate secondary host cell specificity, reactivation, and virulence in their natural hosts. The Polyomaviridae comprise more than 70 polyomavirus (PyV) members, including at least 13 human PyV (HPyV) species (1). HPyV seroprevalence data obtained using the major capsid prote...

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Section: Discussionmentioning

confidence: 99%

Imperfect Symmetry of Sp1 and Core Promoter Sequences Regulates Early and Late Virus Gene Expression of the Bidirectional BK Polyomavirus Noncoding Control Region

Bethge

Ajuh

Hirsch

2016

J Virol

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“…JCPyV DNA could also be detected in some extraneural tissues of the HIV-infected patients, which was most frequent in lymph node (34%) and spleen (26%), also bone (18%), but unexpectedly low in kidney (9%). In the HIV-negative individuals, the overall detection rates were lower, but included spleen and bone being positive for JCPyV DNA, but not for LTag protein (195). Analysis of the NCCR identified mostly rr-NCCR rearrangements in brain tissues of the HIV-positive patients with and without PML as well as some archetype NCCR in the spleen and kidney.…”

Section: Jcpyv Diseasementioning

confidence: 99%

“…During primary viremia, a variety of tissues and cells are potentially exposed to JCPyV, permitting infection of non-renal cells and organs including lymphocytes, progenitorstem, and stroma cells in the bone marrow, tonsils, enteric lymph nodes, and spleen, and possibly also the CNS. The detection of JCPyV genomes by PCR has been reported in many of these sites, although formal evidence of relevant site of JCPyV reactivation and its contribution to PML is lacking (138,(193)(194)(195)(196).…”

Section: Jcpyv Diseasementioning

confidence: 99%

The human JC polyomavirus (JCPyV): virological background and clinical implications

Hirsch

Kardas

Kranz

et al. 2013

APMIS

147

169

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JC polyomavirus (JCPyV) was the first of now 12 PyVs detected in humans, when in 1964, PyV particles were revealed by electron microscopy in progressive multifocal leukoencephalopathy (PML) tissues. JCPyV infection is common in 35–70% of the general population, and the virus thereafter persists in the renourinary tract. One third of healthy adults asymptomatically shed JCPyV at approximately 50 000 copies/mL urine. PML is rare having an incidence of <0.3 per 100 000 person years in the general population. This increased to 2.4 per 1000 person years in HIV‐AIDS patients without combination antiretroviral therapy (cART). Recently, PML emerged in multiple sclerosis patients treated with natalizumab to 2.13 cases per 1000 patients. Natalizumab blocks α4‐integrin‐dependent lymphocyte homing to the brain suggesting that not the overall cellular immunodeficiency but local failure of brain immune surveillance is a pivotal factor for PML. Recovering JCPyV‐specific immune control, e.g., by starting cART or discontinuing natalizumab, significantly improves PML survival, but is challenged by the immune reconstitution inflammatory syndrome. Important steps of PML pathogenesis are undefined, and antiviral therapies are lacking. New clues might come from molecular and functional profiling of JCPyV and PML pathology and comparison with other replicative pathologies such as granule cell neuronopathy and (meningo‐)encephalitis, and non‐replicative JCPyV pathology possibly contributing to some malignancies. Given the increasing number of immunologically vulnerable patients, a critical reappraisal of JCPyV infection, replication and disease seems warranted.

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“…However, viral reactivation in kidneys or blood preceding its migration to the brain is controversial since different groups have found viruses in brain of healthy individuals 16,17 as well as no viremia at all in some affected patients. It was also found latent JCV in lymph, spleen, bone marrow and tonsil demonstrating that the virus may establishes latency in many tissues 18,19 .…”

Section: A Short Background Of Pmlmentioning

confidence: 99%

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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JC Virus Latency in the Brain and Extraneural Organs of Patients with and without Progressive Multifocal Leukoencephalopathy

Cited by 106 publications

References 31 publications

Imperfect Symmetry of Sp1 and Core Promoter Sequences Regulates Early and Late Virus Gene Expression of the Bidirectional BK Polyomavirus Noncoding Control Region

Imperfect Symmetry of Sp1 and Core Promoter Sequences Regulates Early and Late Virus Gene Expression of the Bidirectional BK Polyomavirus Noncoding Control Region

The human JC polyomavirus (JCPyV): virological background and clinical implications

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

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