
Progressive Multifocal Leukoencephalopathy
Wednesday, June 19, 2013 - Thursday, June 20, 2013
Presented By
Progressive Multifocal Leukoencephalopathy (PML) is, in the general population, a rare but serious demyelinating disease of the brain, often resulting in severe disability or death and is caused by infection of oligodendrocytes by the JC polyomavirus (JCV). It is believed that fifty to sixty percent of the population is sero-positive for JCV, indicating exposure to the virus. Despite the high prevalence of JCV infection in the human population, which typically leads to a chronic, asymptomatic infection, incidence of PML in the general population is very low. The pathogenesis of PML is not well understood. It is believed that the development of PML, while dependent on the presence of JCV, is the result of a confluence of viral and host risk factors, which may include an altered or compromised immune system such as in individuals with HIV-1 infection/acquired immune deficiency syndrome (AIDS), or patients undergoing chronic immunosuppressive therapies after organ transplantation, for treatment of lymphomas, or for autoimmune conditions, such as MS.
This 2-day conference will bring together basic science researchers, clinicians, physicians, epidemiologists, and regulatory experts from academia, industry, and government to address novel issues, current challenges, and future directions of basic and clinical research relevant to the mitigation, potential future cure, and risk stratification of PML. Topics of discussion will include JCV virology, PML pathogenesis, risk stratification and disease diagnosis and management. The meeting will feature a series of plenary lectures, short talk presentations selected from submitted abstracts, a poster session, and a closing panel discussion.
Conference Planning Committee
Claudio Carini, MD
Pfizer Inc.
Teresa Compton, PhD
Biogen Idec (Conference Chair)
Marion Kasaian, PhD
Pfizer Inc.
Theodora Salcedo, PhD
Bristol-Myers Squibb Company
Anne Vogt, PhD
F. Hoffmann-La Roche Ltd
Scientific Advisory Board
Leonard H. Calabrese, DO
Cleveland Clinic
Paola Cinque, MD, PhD
San Raffaele Scientific Institute
David B. Clifford, MD
Washington University School of Medicine
Robert L. Garcea, MD
University of Colorado at Boulder
Eugene O. Major, PhD
National Institute of Neurological Disorders and Stroke
Kenneth Tyler, MD
University of Colorado School of Medicine
Thomas Weber, MD
University of Hamburg
Registration Pricing
By 5/13/2013 | After 5/13/2013 | Onsite | |
Member | $125 | $150 | $175 |
Student/Postdoc Member | $75 | $100 | $125 |
Nonmember (Academia) | $150 | $185 | $225 |
Nonmember (Corporate) | $185 | $225 | $265 |
Nonmember (Non-profit) | $150 | $185 | $225 |
Nonmember (Student / Postdoc / Fellow) | $75 | $100 | $125 |
Registration includes a complimentary, one-year membership to the New York Academy of Sciences. Complimentary memberships are provided to non-members only and cannot be used to renew or extend existing or expiring memberships. A welcome email will be sent upon registration which will include your membership credentials.
Presented by
Agenda
* Presentation titles and times are subject to change.
Day 1: June 19, 2013 | |||
8:00 AM | Breakfast and Registration | ||
8:45 AM | Welcoming Remarks | ||
9:00 AM | Keynote Address: Natalizumab-associated PML | ||
Session 1: JCV Virology
| |||
9:45 AM | Infectious Entry of JCPyV into Host Cells | ||
10:15 AM | Leu/Ile/Phe-rich Domain of JC Virus Agnoprotein Plays Important Regulatory Roles in Dimer/Oligomer Formation, Protein Stability and Splicing of The Viral Transcripts | ||
10:45 AM | Networking Break | ||
11:15 AM | Virion Assembly Factories in Polyoma-Infected Cells | ||
11:45 AM | Cell Type Differences in Chromatin Structure of JC Virus Indicate that Repressive Factors Determine Levels of Viral Transcription | ||
12:00 PM | PML-Associated Mutations in the JC Polyomavirus Capsid Disrupt LSTc Binding | ||
12:15 PM | JC Virus Intranuclear Inclusins Associated with Promyelocytic Leukemia Protein Nuclear Bodies | ||
12:30 PM | Networking Lunch | ||
1:30 PM | Patient Keynote Address: A Patient and Family Perspective on PML | ||
Session 2: Pathogenesis
| |||
2:00 PM | Immunology of PML | ||
2:30 PM | Viral Determinants of PML Pathogenesis | ||
3:00 PM | Networking Break | ||
3:30 PM | Virus-Host Interactions — Lessons from the BK Virus | ||
4:00 PM | T Lymphocyte-mediated Cellular Immune Response against JC Virus in PML Patients | ||
4:30 PM | Antibody-Mediated Neutralization of PML-Associated JCV Mutants | ||
4:45 PM | Development of a Mouse Model of Polyomavirus-Induced Central Nervous System Disease | ||
5:00 PM | JC Virus Infection in a Humanized Mouse Model | ||
5:15 PM | Development of a Nonhuman Primate Model of Polyomavirus Disease in Bolivian Squirrel Monkeys | ||
5:30 PM | Poster Session and Networking Reception | ||
7:00 PM | Day 1 Close | ||
Day 2, June 20, 2013 | |||
8:00 AM | Breakfast | ||
8:45 AM | Welcoming Remarks | ||
Session 3: Risk Stratification
| |||
9:00 AM | Are B-cells a Reservoir of JC Virus? | ||
9:30 AM | What Have We Learned From Natalizumab and PML Risk Stratification? | ||
10:00 AM | Risk Stratification in the MS Patient Population | ||
10:30 AM | Networking Break | ||
11:00 AM | Patients with PML Display Low BKV Antibody Reactivity: Potential Implications for PML Risk Stratification | ||
11:15 AM | Host Genetic Contribution to Development of PML in the Presence of Immune Suppression or Immune-Modulating Drugs | ||
11:30 AM | Standardization of Serology DATA for Probability-Based JCV Antibody Determination | ||
11:45 PM | Infection With JC Virus is Strongly Controlled by Human Leukocyte Antigen Class in Variants | ||
12:00 PM | Networking Lunch | ||
Session 4: Diagnosis & Management of PML
| |||
1:30 PM | Immune Reconstitution Inflammatory Syndrome | ||
2:00 PM | Magnetic Resonance Imaging Findings in Progressive Multifocal Leukoencephalopathy in Natalizumab-Treated MS Patients | ||
2:30 PM | PML Clinical Trials | ||
3:00 PM | Pathology of Immune Reconstitution Inflammatory Syndrome in Multiple Sclerosis With Natalizumab-Associated Progressive Multifocal Leukoencephalopathy | ||
3:30 PM | Networking Break | ||
4:00 PM | Human-Derived Antibodies Targeting JCV as Therapeutic Agents for the Management of PML | ||
4:15 PM | Eleven Non-Fatal Outcomes in Natalizumab-Associated PML/IRIS: The Effects of Early Diagnosis and Novel Therapeutic Approaches | ||
Session 5: Closing Session | |||
4:30 PM | JCV and PML: Studies at the Intersection of the Immune and Nervous Systems | ||
4:40 PM | Panel Discussion: The Future of PML | ||
5:30 PM | Conference Adjourns |
Abstracts — Day 1: Wednesday, June 19, 2013
Keynote Address: Natalizumab-Associated PML
Alfred W. Sandrock, Jr, MD, PhD, Biogen Idec
SESSION I: JCV Virology
Infectious Entry of JCPyV into Host Cells
Walter J. Atwood, PhD, Brown University
Co-authors: Christian D.S. Nelson, PhD, Dan Carney, BS, Aaron Derdowski, PhD, Paul Williard, PhD, Jason Sello, PhD, Brown University
Leu/Ile/Phe-rich Domain of JC Virus Agnoprotein Plays Important Regulatory Roles in Dimer/Oligomer Formation, Protein Stability and Splicing of the Viral Transcripts
Mahmut Safak, PhD, Temple University School of Medicine
Understanding the molecular mechanisms underlying the functional roles of agnoprotein in JCV life cycle is still at infancy, in spite of much progress made in this respect. We have recently reported that agnoprotein forms stable dimer/oligomers mediated by a predicted an amphipathic α-helix, spanning amino acids (aa) 17 to 42. Deletion of the α-helix renders a replication incompetent virus. We have now further characterized this region by a systematic deletion and substitution mutagenesis and demonstrated that a Leu/Ile/Phe-rich domain (spanning aa 28-39) within the α-helix is critical for its structure and function. For instance, deletion of aa 30-37, severely affects the dimer/oligomer formation and stable expression of the protein. Mutagenesis data also revealed that in the absence of aa 34-36, the mutant virus exhibits defects in splicing of the viral transcripts, suggesting a novel regulatory role for agnoprotein in JCV gene regulation at the post-transcriptional level.
In addition, due to the basic amino acid composition and nucleocytoplasmic localization of agnoprotein, we reason that this protein may interact with JCV mRNA and be involved in export of the viral RNA from nucleus to cytoplasm. Indeed, our recent in vivo RNA-CHIP analysis revealed a specific interaction between agnoprotein and JCV RNA. Moreover, treatment of the infected cells with chromosomal region maintenance 1 (CRM1) inhibitor, Leptomycin B, resulted in a high level of accumulation of agnoprotein in the nucleus, suggesting involvement of agnoprotein in regulation of nucleocytoplasmic export of viral transcripts in a CRM1-dependent manner. Collectively, these findings demonstrate that the Leu/Ile/Phe-rich domain is critically important for the dimer/oligomer formation, stability and function of agnoprotein and thus represents a potential target for developing novel therapeutic agents for progressive multifocal leukoencephalopathy.
Co-author: Sami Saribas, PhD, Temple University School of Medicine
Virion Assembly Factories in Polyoma-Infected Cells
Robert L. Garcea, MD, University of Colorado, Boulder
To investigate the composition of these nuclear factories, we have analyzed the localization of viral and cellular proteins using confocal immunofluorescence microscopy, and replicating viral DNA using fluorescent in-situ hybridization (FISH). We have found that foci of replicating MPyV DNA co-localize with the viral T-antigen during early infection, and these foci expand as infection proceeds. Co-localizing to these sites of viral DNA we observed cell DNA repair proteins, such as Mre11 and Nbs1, and γH2A.x, along with activation of ATM kinase and CHK1. Inhibitors of ATM, Mre11, and Chk2 all reduce virus outputs. These observations support the view that polyomavirus replication utilizes the cellular DNA damage repair pathways for efficient viral DNA replication, as well as blocking the cell in cycle at the S to G2 stage, allowing continued access of viral replication to critical cellular factors.
Short Talks Selection
Cell Type Differences in Chromatin Structure of JC Virus Indicate that Repressive Factors Determine Levels of Viral Transcription
Michael W. Ferenczy, PhD, National Institute of Neurological Disorders and Stroke
Co-author: Eugene O. Major, PhD, National Institute of Neurological Disorders and Stroke
PML-Associated Mutations in the JC Polyomavirus Capsid Disrupt LSTc Binding
Melissa S. Maginnis,PhD1 JC polyomavirus (JCPyV) is a ubiquitous human pathogen and the causative agent of the fatal, demyelinating disease Progressive Multifocal Leukoencephalopathy (PML). We have previously demonstrated that the JCPyV prototype strain Mad-1 binds specifically to alpha-2,6-linked lactoseries tetrasaccharide c (LSTc) to initiate infection of host cells. Specific residues in the viral capsid protein VP1 are responsible for mediating direct interactions with the a2,6-linked sialic acid of LSTc. Viral isolates from individuals with PML often contain mutations in the sialic acid-binding pocket of VP1 that are thought to arise from positive selection. We reconstituted these mutations in the Mad-1 strain of JCPyV and found that they were not capable of growth. The mutations were then introduced into recombinant VP1 and reconstituted as purified pentamer subunits in order to conduct binding studies and structural analyses. VP1 pentamers carrying PML-associated mutations were not capable of binding to permissive cells. High-resolution structural analysis revealed that these pentamers are properly folded but no longer bind to LSTc due to steric clashes in the sialic acid binding site. Reconstitution of the mutations into a JCPyV pseudovirus expression system revealed that pseudoviruses with PML-associated mutations were not infectious, nor were they able to engage sialic acid as measured by hemagglutination of human red blood cells. These results demonstrate that viruses from PML patients with single point mutations in VP1 disrupt binding to sialic acid motifs, suggesting that these viruses are either non-infectious or infect cells in a sialic acid-independent manner.
Co-authors: Luisa J. Ströh, MSc2, Gretchen V. Gee, PhD1, Bethany A. O’Hara, MSc1,Aaron Derdowski, PhD1, Thilo Stehle, PhD2,3 and Walter J. Atwood, PhD1; 1Brown University,; 2Interfaculty Institute of Biochemistry, University of Tübingen; 3Vanderbilt University School of Medicine
JC Virus Intranuclear Inclusions Associated with Promyelocytic Leukemia Nuclear Bodies
Yukiko Shishido-Hara, MD, PhD1,2 Progressive multifocal leukoencephalopathy is a fatal demyelinating disorder due to JC virus infection. Histopathologically, the viralinclusions are identified in the markedly enlarged nuclei of glial cells, as two distinctive patterns. The dot-shaped inclusions represent clusters of progeny virions accumulated at subnuclear domains called promyelocytic leukemia nuclear bodies (PML-NBs), while the full inclusions reflect the progenies dispersed to the entire part of the nucleoplasm. We analyzed JC virus capsid formation in use of a eukaryotic expression system providing virus-like particles (VLPs), and viral inclusions were further investigated in human brain tissues. We found that the major and minor capsid proteins cooperatively transport to the nucleus for capsid assembly at PML-NBs. In the presence of the agnogene, uniform VLPs were formed restrictedly at PML-NBs; while when the 5’ termini of the agnogene(nt 275-409) was deleted, pleomorphic VLPs were more randomly produced in the nucleus besides PML-NBs.The cells harboing VLPs were more severely degraded in the presence of agnogene than its absence. In the human brain tissues, the largest PML-NBs were shaped as spherical shells over 1 μm in diameter.The JC virus capsid proteins circumscribed the PML-NB surface, suggesting the active sites for progeny production.With advancement of demyelination, there appeared more full inclusions, in which PML-NB structures were disrupted. These results indicate that pathogenic JC virus progenies are efficiently re-produced at PML-NBs in the presence of agnogene. The PML-NBmay play important roles for JC viral progeny re-production, and also subsequence death of host glial cells.
Co-authors: Toshiki Uchihara, MD, PhD2, Takuya Yazawa MD, PhD1, Hiroshi Kamma MD, PhD1; 1Kyorin University School of Medicine;2Tokyo Metropolitan Institute of Medical Science
Patient Keynote Address
A Patient and Family Perspective on PML
Declan R. Walsh, Deferno Trust
As part of this journey, I set up the Deferno Trust on behalf of Natalie. It serves to provide information and family support to those affected by Tysabri related PML and provides a medium for those seeking information onimmune reconstitution inflammatory syndrome(IRIS)/PML from a non-medical point of view. I will share some of my experiences in meeting with others that were diagnosed with PML and give a brief summary of the nature of the comments and concerns of those that have been in touch through the website.
Finally, I would like to convey our views on what we, as patients and families, would require from all of the various elements of the medical industry and seek a collaborative approach to ensure that the patients and their families remain at the forefront of the efforts in finding a solution to this incurable disease.
SESSION II: Pathogenesis
Immunology of PMLRoland Martin, MD, University Hospital Zurich, Universität Zürich Immune control of JC polyoma virus (JCV) involves all aspects of the adaptive immune system including JCV-specific B cells/antibodies, CD4+ and CD8+ T cells. In immunocompromised patients, progressive multifocal leukeoencephalopathy (PML) probably develops in a multi-step process including perturbed JCV “homing”, mutation to glio-/neurotropic JCV strains, and compromise of helper (CD4+) and effector T cells (CD8+), and also B cell/antibodies. We have recently characterized the T cell responses in the brain of PML and PML immune reconstitution inflammatory syndrome (PML-IRIS), and also of a first case of cerebellar granule neuronopathy (CGN), which occurred during treatment with natalizumab. Main findings in the brain infiltrate of PML-IRIS are the predominance of CD4+ T cells that are specific for JCV (VP1) epitopes and frequently express a Th1-2 phenotype, i.e., secrete large amounts of interferon-γ and interleukin-4. Most prominently expressed T cell clones in the brain tissue use T cell receptors that are capable of interacting with two or more different HLA/peptide complexes (cross-restricted). In the GCN case, the brain-infiltrating T cells involve clonally expanded CD4+ and CD8+ populations, and T cells that co-express CD8+ and CD4+ appear most important.
Based on our data we reasoned that boosting a protective CD4+ T cell response might be particularly important for improving overall JCV immune control in PML and that this would also aid the effector arms (CD8+ T cells and antibodies). The successful treatment of two PML patients with idiopathic CD4+ lymphopenia and secondary immunocompromise by a combination of recombinant human interleukin-7 (rh-IL-7) and vaccination with JCV VP1 protein and an adjuvant supports our hypothesis. Finally, in a parallel program to develop a passive PML vaccine, we have isolated high affinity human monoclonal antibodies against JCV virus-like particles from PML-IRIS patients. These data indicate that a better understanding of JCV immune control during physiologic conditions and in PML promises to lead to an effective treatment and prophylaxis.
Viral Determinants of PML Pathogenesis
Leonid Gorelik, PhD, Biogen Idec
Virus-Host Interactions — Lessons from the BK Polyomavirus
Hans H. Hirsch, MD, MSc, University of Basel
T Lymphocyte-Mediated Cellular Immune Response against JC Virus in PML Patients
Igor J. Koralnik, MD, Beth Israel Deaconess Medical Center,Harvard University
Despite their low numbers, JCV-specific CD8+ cytotoxic T lymphocytes play a crucial role, and their presence has been associated with a favorable clinical outcome and improved survival. Conversely, T-cells have been implicated in the pathogenesis of the immune reconstitution inflammatory syndrome (IRIS). IRIS is a frequent manifestation in PML patients with AIDS upon starting antiretroviral medications, and occurs in most multiple sclerosis patients with natalizumab-associated PML, after discontinuation of the medication. Indeed, IRIS may lead to brain edema, herniation and death.
We will review the beneficial and potentially deleterious effects of the cellular immune response in PML patients with and without IRIS, discuss strategies and pitfalls in detecting JCV-specific T cells in blood and central nervous system, as well as implications for the clinical management of these patients.
SHORT TALKS SELECTION
Antibody-Mediated Neutralization of PML-Associated JCV Mutants
Christopher B. Buck, PhD, National Cancer Institute
Co-authors: Upasana Ray, PhD and Diana V. Pastrana, PhD, National Cancer Institute
Development of a Mouse Model of Polyomavirus-Induced Central Nervous System Disease
Elizabeth L. Frost, BS1,2
Co-authors: Aron E. Lukacher, MD, PhD2; 1Emory University; 2The Pennsylvania State University College of Medicine
JC Virus Infection in a Humanized Mouse Model
C. Sabrina Tan, MD1
Co-authors: Thomas Broge Jr, BS1, Edward Seung, PhD2, Vlad Vrbanac, DVM2, Raphael Viscidi, MD3, Jennifer Gordon, PhD4, Andrew M. Tager, MD, PhD2, Igor J. Koralnik, MD1;1Beth Israel Deaconess Medical Center; 2Massachusetts General Hospital, 3Johns Hopkins Medical Center; 4Temple University School of Medicine
Development of a Nonhuman Primate Model of Polyomavirus Disease in Bolivian Squirrel Monkeys
John A. Vanchiere, MD, PhD1
Co-authors: Gloria B. McClure, MS1, Donna L. Rogers, PhD1, Pramod N. Nehete, PhD2, Julio C. Ruiz, DVM2, Mark J. McArthur, DVM2, Wallace B. Baze, DVM, PhD2, Christian R. Abee, DVM2; 1Louisiana State University Health Sciences Center – Shreveport; 2University of Texas M.D. Anderson Cancer Center
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