In contrast to the clinical activity of natalizumab and efalizumab, rituximab targets CD20 receptor on B cells and causes their cytolysis through complement-dependent manner and thereby depletes them from peripheral circulation.
The depletion of B cells by rituximab appears to be relatively rapid compared to the leukocytosis induced by natalixumab and efalizumab, which takes weeks to months. However, in each case of the treatment, there is a clear negative impact of the drug treatment on either humoral or cellular arm of the immune system, which consequently leads to a severe immunosuppression. This provides an opportunity for JCV to reactivate and replicate its genome at the respective sites.
At first glance, one might think that the loss of immune surveillance inherit in these therapies would be a determining factor for reactivation of JCV and onset of PML in a subset of autoimmune patients, who were treated with aforementioned treatments.
However, there appears to be additional critical unknown factors contributing to the onset of the disease, one of which could be the genetic makeup of an individual patient. PML is a rare but fatal CNS disease characterized by demylelination of the neuronal cells leading to severe neurological impairments. Currently, there is no effective drug treatment for PML. The disease is caused by a human polyomavirus, JCV, which was isolated for nearly 38 years ago and latently infects the majority of the human population.
Virulent form of the virus appears to emerge when viral DNA undergoes certain arrangements in its regulatory region in a small population of immunesuppressed individuals.
Although considerable progress has been made with respect to understanding its biology, further studies are required to fully characterize its life cycle, concentrating on studies of the regulatory roles of viral specific regulatory proteins.
Particularly characterization of the role of agnoprotein and Sm t-Ag in viral replication and virion biogenesis will shed further light on the understanding of JCV biology, particularly on the viral reactivation process and the onset of PML. Findings from these studies will further enhance our understanding of the relationship between JCV and PML and may lead the way to discover effective drugs to curb or alleviate the symptoms of this fatal CNS disease.
PML occurs in a small population of immunocompromised patients with an underlying disease such as lymphoproliferative disease, AIDS etc. The most common symptoms of PML are visual and mental deficit and motor weakness. Currently, there is no effective treatment for JCV infection. Treatment of autoimmune diseases with immunomodulatory drugs poses a risk factor for the development of PML.
National Center for Biotechnology Information , U. Future Virol. Author manuscript; available in PMC Jul 1. Author information Copyright and License information Disclaimer. Copyright notice. See other articles in PMC that cite the published article. Clinical features of PML PML is a subcortical white matter disease of the brain and exhibits signs and symptoms indicative of involvement in multiple regions of the brain Fig.
Open in a separate window. Diagnosis and treatment of PML Although PML lesions, caused by both lytic infection of oligodendrocytes and neuronal loss, can be detected by magnetic resonance imaging MRI system [ 33 ], some other CNS related viral infections may make this diagnosis difficult. Viral genome organization The genome of JCV is composed of bidirectional regulatory elements and coding regions Fig.
Oncogenic potential of JCV Following its isolation, oncogenicity of JCV has been demonstrated not only in experimental animals but also in tissue culture [ 10 ]. Conclusions and future perspectives PML is a rare but fatal CNS disease characterized by demylelination of the neuronal cells leading to severe neurological impairments.
Hallervorden J. Eigennartige and nicht rubriziebare prozesse. In: Bumke O, editor. Handbuch der Geiteskranheiten, Vol. Die Anatomie der Phychosen. Springer; Berlin: Progressive multifocal encephalopathy: A hitharto unrecognized complication of chronic lymphocytic leukemia and lymphoma. Cerebral demyelination associated with disorder of thereticuloendothelial system. Particles resembling papovavirus in human cerebral demyelinating disease.
Zu Rhein GM. Association of papovavirions with a human demyelination disease progressive multifocal leukoencephalopathy Prog Med Virol. Cultivation of papova-like virus from human brain with progressive multifocal leukoencephalopathy. First study describing the isolation of JC virus from a patient with progressive multifocal encephalopathy. Human polyomavirus JC virus genome. J Virol. The first sequence information of JC virus was published through this study.
New human papovavirus BK isolated from urine after renal transplantation. Berger JR, Concha M. Progressive multifocal leukoencephalopathy: the evolution of a disease once considered rare.
J Neurovirol. The molecular biology of JC virus, causative agent of progressive multifocal leukoencephalopathy. Humana Press Inc. Pathogenesis and molecular biology of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain.
Clin Microbiol Rev. Evidence that a sequence similar to TAR is important for induction of the JC virus late promoter by human immunodeficiency virus type 1 Tat. Trans-activation of the JC virus late promoter by the tat protein of type 1 human immunodeficiency virus in glial cells. Cullen BR. Frankel AD. Activation of HIV transcription by tat.
Curr Opin Genes Dev. Activation of the JC virus Tat-responsive transcriptional control element by association of the Tat protein of human immunodeficiency virus 1 with cellular protein Pur alpha. Cellular uptake of the Tat protein from human immunodeficiency virus. Microbiol Immunol. SMAD proteins of oligodendroglial cells regulate transcription of JC virus early and late genes coordinately with the Tat protein of human immunodeficiency virus type 1.
J Gen Virol. Cytokines and arachidonic metabolites produced during the human immunodeficiency virus HIV -infected macrophage-astroglia interaction: implications for the neuropathogenesis of HIV disease. J Exp Med.
Gordon J, Khalili K. Human papovavirus JC : induction of brain tumors in hamsters. Progressive multifocal encephalopathy. Neurol Clin. Thomson RA, Jones M. Remission in progressive multifocal leukoencephalopathy. Berger JR. Progressive Multifocal Leukoencephalopathy. Type :. Aliases :. Virut, Win Removal Automatic action Suspect a file is incorrectly detected a False Positive? Automatic action Based on the settings of your F-Secure security product, it will either move the file to the quarantine where it cannot spread or cause harm, or remove it.
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Contact Support Chat with or call an expert for help. Submit a sample Submit a file or URL for further analysis. Technical Details Viruses belonging to this family infect files with. Some Virut variants contain the following text strings: O noon of life! O time to celebrate! Moreover, prior immunosuppressant use in the natalizumab population is decreasing over time. Efforts are ongoing to collect serum or plasma samples from natalizumab-treated patients through Biogen Idec—sponsored clinical studies as well as through collaborations with treating neurologists to further strengthen the observation regarding the association of higher index with PML risk and the effect of immunosuppressants.
Recent analysis of additional samples from natalizumab-treated PML and non-PML patients supports the findings outlined in this paper, and will be a subject of future publication. Future analytical directions may include exploring the value of a longitudinal, continuous model to further improve PML risk estimation over time for an individual patient. This may allow for increased precision in PML risk estimates and for modeling the possible association between different risk factors over time.
Efforts from several other investigators have also been focused on identifying markers to better predict PML risk on an individual-patient basis. Most patients who changed serological status from anti-JCV antibody negative to positive over 18 months maintained a lower index. The stability of PML risk estimates over time based on anti-JCV antibody index continues to be evaluated to confirm these results. The study was funded by Biogen Idec, which also provided funding for editorial support in the development of the manuscript.
Freelance writer Michelle McDermott, PharmD, wrote the first draft of the manuscript based on input from authors, and Joshua Safran of Infusion Communications copyedited and styled the manuscript per journal requirements. Biogen Idec reviewed and provided feedback on the manuscript to the authors. The authors had full editorial control of the manuscript and provided their final approval of all content.
All authors have equity interests in and are currently or were formerly employed by Biogen Idec. National Center for Biotechnology Information , U. Annals of Neurology. Ann Neurol. Published online Oct Author information Article notes Copyright and License information Disclaimer.
E-mail: moc. Annals of Neurology published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
See commentary " Finger pointing to JC virus: a tale of two indexes " in Ann Neurol , volume 76 on page This article has been cited by other articles in PMC. Methods The association between serum or plasma anti-JCV antibody levels and PML risk was examined in anti-JCV antibody—positive multiple sclerosis MS patients from natalizumab clinical studies and postmarketing sources. Open in a separate window. Figure 1. Figure 2. Figure 3. Figure 4.
Index Threshold 0. Figure 5. Discussion The current analysis has extended our prior observations to show that in anti-JCV antibody—positive natalizumab-treated patients, higher levels of serum or plasma anti-JCV antibodies, as measured by anti-JCV antibody index, are associated with higher PML risk.
Acknowledgments The study was funded by Biogen Idec, which also provided funding for editorial support in the development of the manuscript. Authorship T.
Potential Conflicts of Interest All authors have equity interests in and are currently or were formerly employed by Biogen Idec. References 1. But which cells are endowed with such receptors and cofactors? Kahn and Marc A. Schneider discovered that certain progenitor cells in the bronchi are mainly responsible for producing the coronavirus receptors.
These progenitor cells normally develop into respiratory tract cells lined with hair-like projections called cilia that sweep mucus and bacteria out of the lungs. An interesting additional finding of the study was that the ACE2 receptor density on the cells increased with age and was generally higher in men than in women.
However, he points out, "our sample sizes are still much too small to make conclusive statements, so we need to repeat the study in larger patient cohorts. Based on a high-performance technology solution designed by Intel, Dell developed a hardware and system architecture that reduced the processing time needed to sequence the 60, single cells.
Hannes Schwaderer, country manager of Intel Germany, explains: "There are many things we don't know about the coronavirus. This research project and the next steps require enormous computing resources.
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