Progressive multifocal leukoencephalopathy developed 26 years after renal transplantation

Nagayama, Shigemi; Gondo, Yuichiro; Araya, Shinichi; Minato, Naomi; Fujita-Nakata, Michiyo; Kaito, Muichi; Nakanishi, Masao; Tanaka, Keiko; Yamaya, Hideki; Yokoyama, Hitoshi; Nakamichi, Kazuo; Saijo, Masayuki; Okamoto, Kouichirou; Toyoshima, Yasuko; Kakita, Akiyoshi; Matsui, Makoto

doi:10.1016/j.clineuro.2012.11.016

Cited by 8 publications

(3 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the kidney, JCV can replicate sporadically and at low levels in the epithelium of the kidney tubules, from where it can shed from the apical face of the kidney epithelium, leading to viruria and transmission of virions into the environment in the urine (7), completing the normal JCV life cycle. Virus may spread to the bone marrow (8), where it has been postulated but is not proven that neurotropic virus (red) may emerge by an unknown mechanism. Subsequently, JCV may undergo hematogenous spread from the bone marrow and possibly other locations in association with leukocytes (9) to other sites, including the brain (10), where neurotropic JCV DNA can be detected in healthy, immunocompetent individuals in the absence of expression of detectable levels of viral proteins.…”

Section: Early Events In Pathogenesismentioning

confidence: 99%

“…Conflicting hypotheses have been proposed that remain to be resolved, and these will be discussed below. Other therapeutic agents that perturb the immune system, including rituximab, used to treat lymphomas and rheumatoid arthritis (RA), mycophenolate mofetil, and other therapeutic immunosuppressants have also been associated with PML, although their association with PML is not as compelling as with natalizumab and efalizumab . Recently (August 29, 2013), the US Food and Drug Administration (FDA) issued an alert that an MS patient in Europe has developed PML after taking the drug fingolimod (http://www.fda.gov/Drugs/DrugSafety/ucm366529.htm), and the death of a patient from PML while taking Tecfidera for MS was reported on October 31, 2014 (http://www.healthline.com/health-news/patient-taking-tecfidera-for-ms-dies-of-pml-103014).…”

Section: Immunoassays For Jc Virus: Rates Vary Between 33% and 91%mentioning

confidence: 99%

See 1 more Smart Citation

Persistence and pathogenesis of the neurotropic polyomavirus JC

Wollebo

White

Gordon

et al. 2015

Annals of Neurology

118

106

View full text Add to dashboard Cite

Many neurological diseases of the CNS are underpinned by malfunctions of the immune system including disorders involving opportunistic infections. Progressive multifocal leukoencephalopathy (PML) is a lethal CNS demyelinating disease caused by the human neurotropic polyomavirus JC (JCV) and is found almost exclusively in individuals with immune disruption including HIV/AIDS, patients receiving therapeutic immunomodulatory monoclonal antibodies to treat conditions such as multiple sclerosis (MS), transplant recipients, etc. Thus, the public health significance of this disease is high because of the number of individuals that constitute the at-risk population. The incidence of PML is very low whereas seroprevalence for virus is high suggesting infection by virus is very common and so it is thought that virus is restrained but it persists in an asymptomatic state that can only occasionally be disrupted to lead to viral reactivation and PML. When JCV actively replicates in oligodendrocytes and astrocytes of the CNS, it produces cytolysis leading to formation of demyelinated lesions with devastating consequences. Defining the molecular nature of persistence and events leading to reactivation of virus to cause PML has proved to be elusive. In this review, we examine the current state of knowledge of the JCV life cycle and mechanisms of pathogenesis. We will discuss the normal course of the JCV life cycle including transmission, primary infection, viremia and establishment of asymptomatic persistence as well as pathogenic events including migration of virus to the brain, reactivation from persistence, viral infection and replication in the glial cells of the CNS and escape from immunosurveillance.

show abstract

Section: Early Events In Pathogenesismentioning

confidence: 99%

Section: Immunoassays For Jc Virus: Rates Vary Between 33% and 91%mentioning

confidence: 99%

Persistence and pathogenesis of the neurotropic polyomavirus JC

Wollebo

White

Gordon

et al. 2015

Annals of Neurology

118

106

View full text Add to dashboard Cite

show abstract

“…In the 2000s, patients undergoing treatment for autoimmune disorders such as multiple sclerosis and rheumatoid arthritis with new therapeutic immunomodulatory monoclonal antibodies, including natalizumab [ 4 ], efalizumab [ 5 ] and rituximab [ 6 ], led to this class of drugs being recognized as a predisposing factor for PML. Immunosuppressive therapy given to transplant recipients is also a predisposing factor for PML [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

CRISPR/Cas9 System as an Agent for Eliminating Polyomavirus JC Infection

et al. 2015

View full text Add to dashboard Cite

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system (CNS) caused by reactivation of the human polyomavirus JCV gene expression and its replication in oligodendrocytes, the myelin producing cells in the brain. Once a rare disease seen in patients with lymphotproliferative and myeloproliferative disorders, PML has been seen more frequently in HIV-1 positive/AIDS patients as well as patients undergoing immunomodulatory therapy due for autoimmune disorders including multiple sclerosis, rheumatoid arthritis, and others. As of now there is no cure for PML and in most cases disease progression leads to death within two years. Similar to other polyomaviruses, the JCV genome is small circular double stranded DNA that includes coding sequences for the viral early protein, T-antigen, which is critical for directing viral reactivation and lytic infection. Here, we employ a newly developed gene editing strategy, CRISPR/Cas9, to introduce mutations in the viral genome and, by inactivating the gene encoding T-antigen, inhibit viral replication. We first used bioinformatics screening and identified several potential targets within the JCV T-antigen gene that can serve as sites for the creation of guide RNAs (gRNAs) for positioning the Cas9 nuclease on the designated area of the viral genome for editing. Results from a series of integrated genetic and functional studies showed that transient or conditional expression of Cas9 and gRNAs specifically targets the DNA sequences corresponding to the N-terminal region of T-antigen, and by introducing mutation, interferes with expression and function of of the viral protein, hence suppressing viral replication in permissive cells. Results from SURVEYOR assay revealed no off-target effects of the JCV-specific CRISPR/Cas9 editing apparatus. These observations provide the first evidence for the employment of a gene editing strategy as a promising tool for the elimination of the JCV genome and a potential cure for PML.

show abstract

Transmission of Neurotropic Viruses by Transplantation

Chapman

2016

Neurotropic Viral Infections

View full text Add to dashboard Cite

Progressive multifocal leukoencephalopathy developed 26 years after renal transplantation

Cited by 8 publications

References 5 publications

Persistence and pathogenesis of the neurotropic polyomavirus JC

Persistence and pathogenesis of the neurotropic polyomavirus JC

CRISPR/Cas9 System as an Agent for Eliminating Polyomavirus JC Infection

Transmission of Neurotropic Viruses by Transplantation

Contact Info

Product

Resources

About