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Cortese I, Norato G, Harrington PR, Usher T, Mainardi I, Martin-Blondel G, Cinque P, Major EO, Sheikh V. Biomarkers for progressive multifocal leukoencephalopathy: emerging data for use of JC virus DNA copy number in clinical trials. Lancet Neurol 2024; 23:534-544. [PMID: 38631769 DOI: 10.1016/s1474-4422(24)00099-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 03/01/2024] [Accepted: 03/05/2024] [Indexed: 04/19/2024]
Abstract
Progressive multifocal leukoencephalopathy is a rare but devastating demyelinating disease caused by the JC virus (JCV), for which no therapeutics are approved. To make progress towards addressing this unmet medical need, innovations in clinical trial design are needed. Quantitative JCV DNA in CSF has the potential to serve as a valuable biomarker of progressive multifocal leukoencephalopathy disease and treatment response in clinical trials to expedite therapeutic development, as do neuroimaging and other fluid biomarkers such as neurofilament light chain. Specifically, JCV DNA in CSF could be used in clinical trials as an entry criterion, stratification factor, or predictor of clinical outcomes. Insights from the investigation of candidate biomarkers for progressive multifocal leukoencephalopathy might inform approaches to biomarker development for other rare diseases.
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Affiliation(s)
- Irene Cortese
- Experimental Immunotherapeutics Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
| | - Gina Norato
- Clinical Trials Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Patrick R Harrington
- Division of Antivirals, Office of Infectious Diseases, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Therri Usher
- Division of Biometrics IV, Office of Biostatistics, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Ilaria Mainardi
- Unit of Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Guillaume Martin-Blondel
- Service des Maladies Infectieuses et Tropicales, Centre Hospitalier Universitaire de Toulouse, Toulouse, France; Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), INSERM UMR1291-CNRS UMR5051, Université Toulouse III, Toulouse, France
| | - Paola Cinque
- Unit of Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Eugene O Major
- Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Virginia Sheikh
- Division of Antivirals, Office of Infectious Diseases, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
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Ligero-López J, Sánchez-Castellano MÁ, Falces-Romero I, Montero-Vega MD, García-Rodríguez J. Progressive multifocal leukoencephalopathy: a retrospective study of the last 12 years in a tertiary-care hospital. J Neurovirol 2023; 29:598-604. [PMID: 37470903 DOI: 10.1007/s13365-023-01158-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 06/14/2023] [Accepted: 07/05/2023] [Indexed: 07/21/2023]
Abstract
Our study aims to report on the demographic, incidence rate (IR), clinical, and microbiological characteristics of PML patients diagnosed in our tertiary-care hospital over the past 12 years. In this retrospective observational study, we reviewed all requests for JCPyV PCR in CSF from patients with suspected PML. We collected demographic, clinical, and microbiological data of patients diagnosed with PML. Since 2018, real-time quantitative PCR has been used, whereas prior to 2018, samples were sent to our National Reference Center for qualitative diagnosis. Thirteen patients were diagnosed with PML, with 10 of them having a definitive diagnosis and 3 classified as a possible diagnosis with negative PCR results. Eleven patients had advanced HIV, one had non-Hodgkin's lymphoma, and one had systemic lupus erythematosus. Most of the white matter lesions were located at the cerebral level, although the parenchyma and cerebellum were also affected. The most frequent symptoms were behavioral disorders and hemiparesis. The viral load of JCPyV in cerebrospinal fluid was < 1000 copies/mL in three patients. Six patients received compassionate treatment, and all six patients with definitive PML diagnosis died. Although advanced HIV patients were the most affected by PML in our study, it should also be considered in patients with other underlying diseases. While current PCR tests offer high sensitivity and specificity, false negatives can occur. The prognosis of the disease remains poor, and early multidisciplinary diagnosis-including clinical, microbiological, and neuroimaging assessments-remains crucial for improving neurological damage and prognosis.
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Affiliation(s)
- Jorge Ligero-López
- Clinical Microbiology and Parasitology Department, Hospital Universitario La Paz, Paseo de La Castellana 261, 28046, Madrid, Spain.
| | - Miguel Ángel Sánchez-Castellano
- Clinical Microbiology and Parasitology Department, Hospital Universitario La Paz, Paseo de La Castellana 261, 28046, Madrid, Spain
| | - Iker Falces-Romero
- Clinical Microbiology and Parasitology Department, Hospital Universitario La Paz, Paseo de La Castellana 261, 28046, Madrid, Spain
- CIBERINFEC, Instituto de Salud Carlos III, Madrid, Spain
| | - María Dolores Montero-Vega
- Clinical Microbiology and Parasitology Department, Hospital Universitario La Paz, Paseo de La Castellana 261, 28046, Madrid, Spain
| | - Julio García-Rodríguez
- Clinical Microbiology and Parasitology Department, Hospital Universitario La Paz, Paseo de La Castellana 261, 28046, Madrid, Spain
- CIBERINFEC, Instituto de Salud Carlos III, Madrid, Spain
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Rapid-progressing progressive multifocal leukoencephalopathy in two patients newly diagnosed with HIV: case series and review of literature. J Neurovirol 2023; 29:8-14. [PMID: 36774452 PMCID: PMC10089993 DOI: 10.1007/s13365-023-01115-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 01/15/2023] [Accepted: 01/21/2023] [Indexed: 02/13/2023]
Abstract
The JC Polyomavirus (JCPyV) is a virus of global distribution and is usually kept under control by the immune system. In patients with AIDS, a latent JCPyV infection can reactivate and develop into progressive multifocal leukoencephalopathy (PML). Around half of the patients with PML die within 2 years since the diagnosis, yet in rare cases, the disease advances significantly quicker and seems to be insusceptible to any medical actions. In our clinic, we observed two cases of such course in HIV-positive patients in the AIDS stage. On admission, both patients had mild neurological symptoms such as dizziness, vision disturbances, and muscle weakness. Both had extremely low CD4 lymphocyte count (7 cells/μL, 40 cells/μL) and high HIV-1 viral load (VL) (50,324 copies/ml, 78,334 copies/ml). PML was confirmed by PCR for JCPyV DNA in cerebrospinal fluid (CSF) coupled with clinical and radiological features. Despite receiving though antiretroviral (ARV) treatment paired with intra-venous (IV) steroids, the disease progressed rapidly with neurological manifestations exacerbating throughout the few weeks following the admission. Eventually, both patients developed respiratory failure and died within less than 3 months after the onset of the neurological symptoms. Even though such curse of the disease is not common, it should be a warning to all how deadly both PML and AIDS can be and remind doctors to offer testing even to asymptomatic patients.
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Diamantopoulos PT, Kalopisis K, Tsatsou A, Efthymiou A, Giannakopoulou N, Hatzidavid S, Viniou NA. Progressive multifocal leukoencephalopathy in the context of newer therapies in hematology and review of new treatment strategies. Eur J Haematol 2022; 108:359-368. [PMID: 35100451 DOI: 10.1111/ejh.13751] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 01/25/2022] [Accepted: 01/27/2022] [Indexed: 02/07/2023]
Abstract
Progressive multifocal leukoencephalopathy (PML) is a rare, often fatal demyelinating disease of the central nervous system (CNS) caused by the reactivation of JC polyomavirus in the CNS. We present a case of a 54-year-old man with follicular lymphoma diagnosed with PML after being treated with anti-CD20 monoclonal antibody-based regimens for several years. Due to the lack of effective treatment choices for PML, the patient was treated with nivolumab, based on recent reports, but succumbed to his disease a few months after diagnosis. In this paper, we focus on reviewing the literature of PML cases correlated with newer agents used in hematology, possible factors affecting disease prognosis, as well as the available data on upcoming therapeutic options for patients with PML. Though newer promising treatments such as anti-PD1 monoclonal antibodies arise, a definitive treatment option is yet to be found. Vigilance, early detection, and prompt intervention play a crucial role in the prognosis of PML in patients with hematological malignancies.
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Affiliation(s)
- Panagiotis T Diamantopoulos
- First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantinos Kalopisis
- First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Athina Efthymiou
- Department of Neurology, Laikon General Hospital, Athens, Greece
| | - Nefeli Giannakopoulou
- First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Sevastianos Hatzidavid
- First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Nora-Athina Viniou
- First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
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Nakamichi K, Shimokawa T. Database and Statistical Analyses of Transcription Factor Binding Sites in the Non-Coding Control Region of JC Virus. Viruses 2021; 13:v13112314. [PMID: 34835120 PMCID: PMC8620444 DOI: 10.3390/v13112314] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/16/2021] [Accepted: 11/17/2021] [Indexed: 12/26/2022] Open
Abstract
JC virus (JCV), as an archetype, establishes a lifelong latent or persistent infection in many healthy individuals. In immunocompromised patients, prototype JCV with variable mutations in the non-coding control region (NCCR) causes progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease. This study was conducted to create a database of NCCR sequences annotated with transcription factor binding sites (TFBSs) and statistically analyze the mutational pattern of the JCV NCCR. JCV NCCRs were extracted from >1000 sequences registered in GenBank, and TFBSs within each NCCR were identified by computer simulation, followed by examination of their prevalence, multiplicity, and location by statistical analyses. In the NCCRs of the prototype JCV, the limited types of TFBSs, which are mainly present in regions D through F of archetype JCV, were significantly reduced. By contrast, modeling count data revealed that several TFBSs located in regions C and E tended to overlap in the prototype NCCRs. Based on data from the BioGPS database, genes encoding transcription factors that bind to these TFBSs were expressed not only in the brain but also in the peripheral sites. The database and NCCR patterns obtained in this study could be a suitable platform for analyzing JCV mutations and pathogenicity.
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Affiliation(s)
- Kazuo Nakamichi
- Department of Virology 1, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
- Correspondence:
| | - Toshio Shimokawa
- Department of Medical Data Science, Graduate School of Medicine, Wakayama Medical University, Wakayama 641-8509, Japan;
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Cortese I, Reich DS, Nath A. Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease. Nat Rev Neurol 2020; 17:37-51. [PMID: 33219338 PMCID: PMC7678594 DOI: 10.1038/s41582-020-00427-y] [Citation(s) in RCA: 193] [Impact Index Per Article: 38.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/13/2020] [Indexed: 02/06/2023]
Abstract
Progressive multifocal leukoencephalopathy (PML) is a devastating CNS infection caused by JC virus (JCV), a polyomavirus that commonly establishes persistent, asymptomatic infection in the general population. Emerging evidence that PML can be ameliorated with novel immunotherapeutic approaches calls for reassessment of PML pathophysiology and clinical course. PML results from JCV reactivation in the setting of impaired cellular immunity, and no antiviral therapies are available, so survival depends on reversal of the underlying immunosuppression. Antiretroviral therapies greatly reduce the risk of HIV-related PML, but many modern treatments for cancers, organ transplantation and chronic inflammatory disease cause immunosuppression that can be difficult to reverse. These treatments — most notably natalizumab for multiple sclerosis — have led to a surge of iatrogenic PML. The spectrum of presentations of JCV-related disease has evolved over time and may challenge current diagnostic criteria. Immunotherapeutic interventions, such as use of checkpoint inhibitors and adoptive T cell transfer, have shown promise but caution is needed in the management of immune reconstitution inflammatory syndrome, an exuberant immune response that can contribute to morbidity and death. Many people who survive PML are left with neurological sequelae and some with persistent, low-level viral replication in the CNS. As the number of people who survive PML increases, this lack of viral clearance could create challenges in the subsequent management of some underlying diseases. In this Review, Cortese et al. provide an overview of the pathobiology and evolving presentations of progressive multifocal leukoencephalopathy and other diseases caused by JC virus, and discuss emerging immunotherapeutic approaches that could increase survival.
Progressive multifocal leukoencephalopathy (PML) is a rare, debilitating and often fatal disease of the CNS caused by JC virus (JCV). JCV establishes asymptomatic, lifelong persistent or latent infection in immune competent hosts, but impairment of cellular immunity can lead to reactivation of JCV and PML. PML most commonly occurs in patients with HIV infection or lymphoproliferative disease and in patients who are receiving natalizumab for treatment of multiple sclerosis. The clinical phenotype of PML varies and is shaped primarily by the host immune response; changes in the treatment of underlying diseases associated with PML have changed phenotypes over time. Other clinical manifestations of JCV infection have been described, including granule cell neuronopathy. Survival of PML depends on reversal of the underlying immunosuppression; emerging immunotherapeutic strategies include use of checkpoint inhibitors and adoptive T cell transfer.
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Affiliation(s)
- Irene Cortese
- Neuroimmunology Clinic, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
| | - Daniel S Reich
- Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Avindra Nath
- Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
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Jmii H, Fisson S, Aouni M, Jaidane H. Type B coxsackieviruses and central nervous system disorders: critical review of reported associations. Rev Med Virol 2020; 31:e2191. [PMID: 33159700 DOI: 10.1002/rmv.2191] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 10/12/2020] [Accepted: 10/19/2020] [Indexed: 11/07/2022]
Abstract
Type B coxsackieviruses (CV-B) frequently infect the central nervous system (CNS) causing neurological diseases notably meningitis and encephalitis. These infections occur principally among newborns and children. Epidemiological studies of patients with nervous system disorders demonstrate the presence of infectious virus, its components, or anti-CV-B antibodies. Some experimental studies conducted in vitro and in vivo support the potential association between CV-B and idiopathic neurodegenerative diseases such as amyotrophic lateral sclerosis and psychiatric illness such as schizophrenia. However, mechanisms explaining how CV-B infections may contribute to the genesis of CNS disorders remain unclear. The proposed mechanisms focus on the immune response following the viral infection as a contributor to pathogenesis. This review describes these epidemiological and experimental studies, the modes of transmission of CV-B with an emphasis on congenital transmission, the routes used by CV-B to reach the brain parenchyma, and plausible mechanisms by which CV-B may induce CNS diseases, with a focus on potential immunopathogenesis.
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Affiliation(s)
- Habib Jmii
- Laboratory of Transmissible Diseases and Biologically Active Substances LR99ES27, Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
- Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Sylvain Fisson
- Généthon, Inserm UMR_S951, Univ Evry, University Paris Saclay, Evry, France
- Sorbonne University, INSERM, CNRS, Institut de la Vision, Paris, France
| | - Mahjoub Aouni
- Laboratory of Transmissible Diseases and Biologically Active Substances LR99ES27, Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
| | - Hela Jaidane
- Laboratory of Transmissible Diseases and Biologically Active Substances LR99ES27, Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
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Prezioso C, Bianchi M, Obregon F, Ciotti M, Sarmati L, Andreoni M, Palamara AT, Pascarella S, Moens U, Pietropaolo V. Structural Analysis of Merkel Cell Polyomavirus (MCPyV) Viral Capsid Protein 1 (VP1) in HIV-1 Infected Individuals. Int J Mol Sci 2020; 21:7998. [PMID: 33121182 PMCID: PMC7663277 DOI: 10.3390/ijms21217998] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/20/2020] [Accepted: 10/24/2020] [Indexed: 12/12/2022] Open
Abstract
Merkel cell polyomavirus (MCPyV) viral protein 1 (VP1) is the capsid protein that mediates virus attachment to host cell receptors and is the major immune target. Given the limited data on MCPyV VP1 mutations, the VP1 genetic variability was examined in 100 plasma and 100 urine samples from 100 HIV+ individuals. Sequencing of VP1 DNA in 17 urine and 17 plasma specimens, simultaneously MCPyV DNA positive, revealed that 27 samples displayed sequences identical to VP1 of MCC350 strain. VP1 from two urine specimens had either Thr47Ser or Ile115Phe substitution, whereas VP1 of one plasma contained Asp69Val and Ser251Phe substitutions plus deletion (∆) of Tyr79. VP1 DNA in the remaining samples had mutations encoding truncated protein. Three-dimensional prediction models revealed that Asp69Val, Ser251Phe, and Ile115Phe caused neutral effects while Thr47Ser and Tyr79∆ produced a deleterious effect reducing VP1 stability. A549 cells infected with urine or plasma samples containing full-length VP1 variants with substitutions, sustained viral DNA replication and VP1 expression. Moreover, medium harvested from these cells was able to infect new A549 cells. In cells infected by samples with truncated VP1, MCPyV replication was hampered. In conclusion, MCPyV strains with unique mutations in the VP1 gene are circulating in HIV+ patients. These strains display altered replication efficiency compared to the MCC350 prototype strain in A549 cells.
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Affiliation(s)
- Carla Prezioso
- IRCSS San Raffaele Pisana, Microbiology of Chronic Neuro-degenerative Pathologies, 00163 Rome, Italy;
- Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, 00185 Rome, Italy;
| | - Martina Bianchi
- Department of Biochemical Sciences “A. Rossi Fanelli”, “Sapienza” University of Rome, 00185 Rome, Italy; (M.B.); (S.P.)
| | - Francisco Obregon
- Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, 00185 Rome, Italy;
| | - Marco Ciotti
- Laboratory of Clinical Microbiology and Virology, Polyclinic Tor Vergata Foundation, 00133 Rome, Italy;
| | - Loredana Sarmati
- Infectious Diseases Clinic, Policlinic Tor Vergata, 00133 Rome, Italy; (L.S.); (M.A.)
- Department of System Medicine, Tor Vergata University of Rome, 00133 Rome, Italy
| | - Massimo Andreoni
- Infectious Diseases Clinic, Policlinic Tor Vergata, 00133 Rome, Italy; (L.S.); (M.A.)
- Department of System Medicine, Tor Vergata University of Rome, 00133 Rome, Italy
| | - Anna Teresa Palamara
- Department of Public Health and Infectious Diseases, Institute Pasteur, Cenci-Bolognetti Foundation, Sapienza University of Rome, 00185 Rome, Italy;
- IRCCS San Raffaele Pisana, Telematic University, 00163 Rome, Italy
| | - Stefano Pascarella
- Department of Biochemical Sciences “A. Rossi Fanelli”, “Sapienza” University of Rome, 00185 Rome, Italy; (M.B.); (S.P.)
| | - Ugo Moens
- Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, 9037 Tromsø, Norway;
| | - Valeria Pietropaolo
- Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, 00185 Rome, Italy;
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Pietropaolo V, Prezioso C, Moens U. Merkel Cell Polyomavirus and Merkel Cell Carcinoma. Cancers (Basel) 2020; 12:E1774. [PMID: 32635198 PMCID: PMC7407210 DOI: 10.3390/cancers12071774] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 06/26/2020] [Accepted: 06/28/2020] [Indexed: 12/12/2022] Open
Abstract
Viruses are the cause of approximately 15% of all human cancers. Both RNA and DNA human tumor viruses have been identified, with Merkel cell polyomavirus being the most recent one to be linked to cancer. This virus is associated with about 80% of Merkel cell carcinomas, a rare, but aggressive cutaneous malignancy. Despite its name, the cells of origin of this tumor may not be Merkel cells. This review provides an update on the structure and life cycle, cell tropism and epidemiology of the virus and its oncogenic properties. Putative strategies to prevent viral infection or treat virus-positive Merkel cell carcinoma patients are discussed.
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Affiliation(s)
- Valeria Pietropaolo
- Department of Public Health and Infectious Diseases, “Sapienza” University, 00185 Rome, Italy; (V.P.); (C.P.)
| | - Carla Prezioso
- Department of Public Health and Infectious Diseases, “Sapienza” University, 00185 Rome, Italy; (V.P.); (C.P.)
- IRCSS San Raffaele Pisana, Microbiology of Chronic Neuro-Degenerative Pathologies, 00166 Rome, Italy
| | - Ugo Moens
- Molecular Inflammation Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø—The Arctic University of Norway, 9037 Tromsø, Norway
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Immunopathology in the brain of mice following vertical transmission of Coxsackievirus B4. Microb Pathog 2020; 140:103965. [PMID: 31904449 DOI: 10.1016/j.micpath.2020.103965] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Accepted: 01/01/2020] [Indexed: 12/15/2022]
Abstract
Coxsackie B viruses (CV-B) are associated with several central nervous system (CNS) disorders. These viruses are predominantly transmitted by fecal-oral route but vertical transmission can also occur. This work attempted to study the immune response ensuing vertical transmission of CV-B to the brain, and its eventual implementation in the brain pathogenesis. To this end, pregnant Swiss albino mice were inoculated with CV-B4 E2 or with sterile medium for control animals. At different ages after birth, brains were collected and analyzed for virus infection, histopathological changes and immune response. Infectious particles were detected in offspring's brain which demonstrates vertical transmission of the virus. This infection is persistent since the long lasting detection of viral RNA in offspring's brain. Some pathological signs including meningitis, edema and accumulation of inflammatory cells within and surrounding the inflammatory areas were observed. Immunoflorescence staining unveiled the presence of T lymphocytes and microgliosis in the sites of lesion for a long period after birth. Multiplex cytokines measurement upon supernatants of in vitro mixed brain cells and extracted mononuclear cells from offspring's brain has demonstrated an elevated secretion of the pro-inflammatory cytokines TNFα, IL-6 and IFNα and the chemokines RANTES and MCP-1. Hence, vertical transmission of CV-B4 and its persistence within offspring's brain can lead to pathological features linked to increased and sustained immune response.
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11
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Milora KA, Rall GF. Interferon Control of Neurotropic Viral Infections. Trends Immunol 2019; 40:842-856. [PMID: 31439415 DOI: 10.1016/j.it.2019.07.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 07/18/2019] [Accepted: 07/18/2019] [Indexed: 12/29/2022]
Abstract
Interferons (IFNs) comprise a pleiotropic family of signaling molecules that are often the first line of defense against viral infection. Inflammatory responses induced by IFN are generally well tolerated during peripheral infections; yet, the same degree of inflammation during infection of the central nervous system (CNS) could be catastrophic. Thus, IFN responses must be modified within the CNS to ensure host survival. In this review, we discuss emerging principles highlighting unique aspects of antiviral effects of IFN protection following neurotropic viral infection, chiefly using new techniques in rodent models. Evaluation of these unique responses provides insights into how the immune system eradicates or controls pathogens, while avoiding host damage. Defining these principles may have direct impact on the development of novel clinical approaches.
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Affiliation(s)
- Katelynn A Milora
- Program in Blood Cell Development and Function, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Glenn F Rall
- Program in Blood Cell Development and Function, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
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12
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JC virus identified in a patient with persistent and severe West Nile virus disease. J Neurovirol 2019; 25:608-611. [DOI: 10.1007/s13365-019-00744-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 02/26/2019] [Accepted: 03/27/2019] [Indexed: 11/26/2022]
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13
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Sanjo N, Nose Y, Shishido-Hara Y, Mizutani S, Sekijima Y, Aizawa H, Tanizawa T, Yokota T. A controlled inflammation and a regulatory immune system are associated with more favorable prognosis of progressive multifocal leukoencephalopathy. J Neurol 2018; 266:369-377. [PMID: 30511098 DOI: 10.1007/s00415-018-9140-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 11/20/2018] [Accepted: 11/24/2018] [Indexed: 01/09/2023]
Abstract
OBJECTIVE In the present study, we analyzed the inflammatory profiles of brain tissues obtained from patients with progressive multifocal leukoencephalopathy (PML) due to John Cunningham (JC) virus infection to identify potential prognostic factors. METHODS The study included seven patients (two men, five women) who had been pathologically diagnosed with PML, and all of whom were HIV negative. Fixed brain samples were analyzed via hematoxylin and eosin (HE) staining and Klüver-Barrera (KB) staining. We then performed immunohistochemistry (IHC) specific to JC virus capsid proteins (VP1 and VP2/3) and lymphocyte surface markers (CD4, CD8, CD138, and PD-1). RESULTS The mean age at onset was 53.4, while the mean duration until biopsy/autopsy was 4.7 months. Four patients were included in the good prognosis (GP) group, while three were included in the poor prognosis (PP) group. Pathological analysis revealed a significantly larger number of CD4-positive T-cell infiltrations (P = .029) in the GP group, along with a preserved CD4:CD8 ratio. Larger numbers of CD138-positive plasma cells were also observed in the GP group (P = .029) than in the PP group. Linear regression analyses revealed a significant association between the numbers of CD138-positive plasma cells and PD-1-positive cells (R2 = 0.80). CONCLUSIONS Viral loads in the cerebrospinal fluid, a controlled inflammatory response mediated by CD4- and CD8-positive T cells, and plasma cells are associated with PML prognosis. Our findings further indicate that regulatory plasma cells may regulate inflammatory T-cell activity via a PD-1/PD-L1 immuno-checkpoint pathway, thereby protecting the uninfected brain from excessive immune-mediated damage during an active JC virus infection.
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Affiliation(s)
- Nobuo Sanjo
- Department of Neurology and Neurological Science, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, 1-5-45 Yushima Bunkyo-ku, Tokyo, 113-8510, Japan.
| | - Yurie Nose
- Department of Neurology and Neurological Science, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, 1-5-45 Yushima Bunkyo-ku, Tokyo, 113-8510, Japan
| | | | - Saneyuki Mizutani
- Department of Internal Medicine (Neurology), Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan
| | - Yoshiki Sekijima
- Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Nagano, Japan
| | - Hitoshi Aizawa
- Department of Neurology, Tokyo Medical University, Tokyo, Japan
| | - Toru Tanizawa
- Department of Pathology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan
| | - Takanori Yokota
- Department of Neurology and Neurological Science, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, 1-5-45 Yushima Bunkyo-ku, Tokyo, 113-8510, Japan
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L’Honneur AS, Leh H, Laurent-Tchenio F, Hazan U, Rozenberg F, Bury-Moné S. Exploring the role of NCCR variation on JC polyomavirus expression from dual reporter minicircles. PLoS One 2018; 13:e0199171. [PMID: 29944671 PMCID: PMC6019678 DOI: 10.1371/journal.pone.0199171] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Accepted: 06/02/2018] [Indexed: 11/19/2022] Open
Abstract
JC virus (JCV), a ubiquitous human polyomavirus, can cause fatal progressive multifocal leukoencephalopathy (PML) in immune compromised patients. The viral genome is composed of two conserved coding regions separated by a highly variable non-coding control region (NCCR). We analyzed the NCCR sequence from 10 PML JCV strains and found new mutations. Remarkably, the NCCR f section was mutated in most cases. We therefore explored the importance of this section in JCV expression in renal (HEK293H) and glioblastoma (U-87MG) cell lines, by adapting the emerging technology of DNA minicircles. Using bidirectional fluorescent reporters, we revealed that impaired NCCR-driven late expression in glioblastoma cells was restored by a short deletion overlapping e and f sections. This study evidenced a relevant link between JCV NCCR polymorphism and cell-type dependent expression. The use of DNA minicircles opens new insights for monitoring the impact of NCCR variation.
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Affiliation(s)
- Anne-Sophie L’Honneur
- Université Paris Descartes, INSERM Paris, France
- Assistance Publique—Hôpitaux de Paris, Hôpital Cochin, Service de Virologie, Paris, France
| | - Hervé Leh
- LBPA, Université Paris Saclay, CNRS, ENS Paris Saclay, Cachan, France
| | | | - Uriel Hazan
- LBPA, Université Paris Saclay, CNRS, ENS Paris Saclay, Cachan, France
| | - Flore Rozenberg
- Université Paris Descartes, INSERM Paris, France
- Assistance Publique—Hôpitaux de Paris, Hôpital Cochin, Service de Virologie, Paris, France
- * E-mail: (FR); (SBM)
| | - Stéphanie Bury-Moné
- Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, Gif-Sur-Yvette, France
- * E-mail: (FR); (SBM)
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Hu C, Huang Y, Su J, Wang M, Zhou Q, Zhu B. Detection and analysis of variants of JC polyomavirus in urine samples from HIV-1-infected patients in China's Zhejiang Province. J Int Med Res 2018; 46:1024-1032. [PMID: 29322824 PMCID: PMC5972266 DOI: 10.1177/0300060517746297] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Objectives Human JC polyomavirus (JCPyV) infection has an increased risk of developing progressive multifocal leukoencephalopathy (PML). Different JCPyV subtypes differ in the virulence with which they cause PML. Currently, the JCPyV infection status and subtype distribution in patients with human immunodeficiency virus-1 (HIV-1) in China are still unclear. This study aimed to investigate the epidemiology and subtype distribution of JCPyV in HIV-1-infected patients in China. Methods Urine samples from 137 HIV-1-infected patients in Zhejiang Province in China were tested for the presence of JCPyV DNA. The detected VP1 sequences were aligned and analysed using BioEdit and MEGA software. Results Among urine samples from HIV-1-infected patients, 67.2% were positive for JCPyV DNA (92/137). Primarily, the type 7 strains of JCPyV were detected, among which 45.5% (15/33) were subtype 7A, 30.3% (10/33) were 7B, and 24.2% (8/33) were 7C. Six nucleotide mutations, as well as one amino acid substitution, were isolated from the patients. Conclusions Urine samples from HIV-1-infected patients from Zhejiang Province show a high JCPyV infection rate. The most common JCPyV strains are subtypes 7A, 7B, and 7C.
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Affiliation(s)
- Caiqin Hu
- Department of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, 71069 College of Medicine, Zhejiang University , Hangzhou, China
| | - Ying Huang
- Department of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, 71069 College of Medicine, Zhejiang University , Hangzhou, China
| | - Junwei Su
- Department of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, 71069 College of Medicine, Zhejiang University , Hangzhou, China
| | - Mengyan Wang
- Department of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, 71069 College of Medicine, Zhejiang University , Hangzhou, China
| | - Qihui Zhou
- Department of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, 71069 College of Medicine, Zhejiang University , Hangzhou, China
| | - Biao Zhu
- Department of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, 71069 College of Medicine, Zhejiang University , Hangzhou, China
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Biology, evolution, and medical importance of polyomaviruses: An update. INFECTION GENETICS AND EVOLUTION 2017. [DOI: 10.1016/j.meegid.2017.06.011] [Citation(s) in RCA: 111] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Oppenheim S. Prognosis in HIV and AIDS #213. J Palliat Med 2016; 19:1114-1115. [DOI: 10.1089/jpm.2016.0206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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Papa N, Zanotta N, Knowles A, Orzan E, Comar M. Detection of Malawi polyomavirus sequences in secondary lymphoid tissues from Italian healthy children: a transient site of infection. Virol J 2016; 13:97. [PMID: 27287743 PMCID: PMC4901423 DOI: 10.1186/s12985-016-0553-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 06/01/2016] [Indexed: 01/22/2023] Open
Abstract
Background The novel Malawi polyomavirus (MWPyV) was initially detected in stool specimens from healthy children and children with gastrointestinal symptoms, mostly diarrhea, indicating that MWPyV might play a role in human gastroenteric diseases. Recently, MWPyV sequences were additionally identified in respiratory secretions from both healthy and acutely ill children suggesting that MWPyV may have a tropism for different human tissues. This study was designed to investigate the possible sites of latency/persistence for MWPyV in a cohort of healthy Italian children. Methods Specimens (n° 500) of tonsils, adenoids, blood, urines and feces, from 200 healthy and immunocompetent children (age range: 1–15 years) were tested for the amplification of the MWPyV LT antigen sequence by quantitative real-time PCR. Samples (n° 80) of blood and urines from 40 age-matched children with autoimmune diseases, were screened for comparison. Polyomaviruses JC/BK and Epstein-Barr Virus (EBV) were also tested as markers of infection in all samples using the same molecular technique. Results In our series of healthy children, MWPyV was detected only in the lymphoid tissues showing a prevalence of 6 % in tonsils and 1 % in adenoids, although with a low viral load. No JCPyV or BKPyV co-infection was found in MWPyV positive samples, while EBV showed a similar percentage of both in tonsils and adenoids (38 and 37 %). Conversely, no MWPyV DNA was detected in stool from babies with gastroenteric syndrome. With regards to autoimmune children, neither MWPyV nor BKPyV were detected in blood, while JCPyV viremia was observed in 15 % (6/40) of children treated with Infliximab. Urinary BKPyV shedding was observed in 12.5 % (5/40) while JCPyV in 100 % of the samples. Conclusions The detection of MWPyV sequences in tonsils and adenoids of healthy children suggests that secondary lymphoid tissues can harbour MWPyV probably as transient sites of persistence rather than actual sites of latency.
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Affiliation(s)
- N Papa
- Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Via dell'Istria 65, 34137, Trieste, Italy
| | - N Zanotta
- Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Via dell'Istria 65, 34137, Trieste, Italy
| | - A Knowles
- Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Via dell'Istria 65, 34137, Trieste, Italy
| | - E Orzan
- Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Via dell'Istria 65, 34137, Trieste, Italy
| | - M Comar
- Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Via dell'Istria 65, 34137, Trieste, Italy. .,Medical Sciences Department, University of Trieste, Piazzale Europa 1, 34128, Trieste, Italy.
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SantaCruz KS, Roy G, Spigel J, Bearer EL. Neuropathology of JC virus infection in progressive multifocal leukoencephalopathy in remission. World J Virol 2016; 5:31-37. [PMID: 26870672 PMCID: PMC4735552 DOI: 10.5501/wjv.v5.i1.31] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 10/10/2015] [Accepted: 12/15/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To investigate the neuropathology of the brain in a rare case of remission following diagnosis of progressive multifocal leukoencephalopathy (PML).
METHODS: Consent from the family for an autopsy was obtained, clinical records and radiograms were retrieved. A complete autopsy was performed, with brain examination after fixation and coronal sectioning at 1 cm intervals. Fourteen regions were collected for paraffin embedding and staining for microscopic analysis. Histologic sections were stained with Luxol blue, hematoxylin/eosin, and immunostained for myelin basic protein, neurofilament, SV40 T antigen and p53. The biopsy material was also retrieved and sections were stained with hematoxylin/eosin and immunostained for SV40 and p53. Sections were examined by American Board of Pathology certified pathologists and images captured digitally.
RESULTS: Review of the clinical records was notable for a history of ulcerative colitis resulting in total colectomy in 1977 and a liver transplant in 1998 followed by immune-suppressive therapy. Neurological symptoms presented immediately, therefore a biopsy was obtained which was diagnosed as PML. Immunotherapy was adjusted and clinical improvement was noted. No subsequent progression was reported. Review of the biopsy demonstrated atypical astrocytes and enlarged hyperchromatic oligodendroglial cells consistent with JC virus infection. Strong SV40 and p53 staining was found in glial cells and regions of dense macrophage infiltration were present. On gross examination of the post-mortem brain, a lesion in the same site as the original biopsy in the cerebellum was identified but no other lesions in the brain were found. Microscopic analysis of this cerebellar lesion revealed a loss of myelin and axons, and evidence of axonal damage. This single burned-out lesion was equivocally positive for SV40 antigen with little p53 staining. Examination of thirteen other brain regions found no other occult sites.
CONCLUSION: Our study reveals residual damage, rare macrophages or other inflammation and minimal evidence of persistent virus. This case demonstrates the possibility of complete remission of PML.
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Delbue S, Elia F, Signorini L, Bella R, Villani S, Marchioni E, Ferrante P, Phan TG, Delwart E. Human polyomavirus 6 DNA in the cerebrospinal fluid of an HIV-positive patient with leukoencephalopathy. J Clin Virol 2015; 68:24-7. [PMID: 26071330 DOI: 10.1016/j.jcv.2015.04.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Revised: 04/17/2015] [Accepted: 04/21/2015] [Indexed: 11/17/2022]
Abstract
BACKGROUND Leukoencephalopathies in HAART-treated, HIV-positive patients include progressive multifocal leukoencephalopathy (PML), a result of lytic infection oligodendrocytes by JC polyomavirus (JCV), and another form characterized by the absence of JCV genome in cerebrospinal fluid (CSF). OBJECTIVES To test the potential viral etiology of JCV-negative leukoencephalopathy. STUDY DESIGN CSF was collected from 43 HIV-positive patients with MRI suggestive of leukoencephalopathies. DNA was isolated and real-time PCR assays for neurotropic viruses (Herpes Simplex Viruses 1/2, Varicella Zoster Virus, Epstein Barr Virus, Human Cytomegalovirus, Human Herpesvirus 6, JCV and HIV) were conducted. CSF from 14 non-reactive cases were subjected to random nucleic acid amplification, deep sequencing, and in silico search for viral sequences. RESULTS JCV genome was detected in the CSF of 19/43 PML patients, HIV genome in the CSF of 5 PML patients including 2 JCV negative patients, and no viruses were detected in 22 patients. Human Polyomavirus 6 (HPyV6) DNA was detected by deep sequencing in one JCV-negative leukoencephalopathy CSF sample. CONCLUSIONS HPyV6 DNA was detected in CSF of a case of demyelinating disease. HPyV6 has not been previously reported in CSF or associated with any disease. Demonstrating a causative role will require further studies.
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Affiliation(s)
- Serena Delbue
- Laboratory of Translational Medicine, Department of Biomedical, Surgical and Dental Sciences, University of Milano, Italy.
| | - Francesca Elia
- Laboratory of Translational Medicine, Department of Biomedical, Surgical and Dental Sciences, University of Milano, Italy
| | - Lucia Signorini
- Laboratory of Translational Medicine, Department of Biomedical, Surgical and Dental Sciences, University of Milano, Italy
| | - Ramona Bella
- Laboratory of Translational Medicine, Department of Biomedical, Surgical and Dental Sciences, University of Milano, Italy
| | - Sonia Villani
- Laboratory of Translational Medicine, Department of Biomedical, Surgical and Dental Sciences, University of Milano, Italy
| | - Enrico Marchioni
- Department of General Neurology, IRCCS National Neurological Institute C. Mondino Foundation, Pavia, Italy
| | - Pasquale Ferrante
- Laboratory of Translational Medicine, Department of Biomedical, Surgical and Dental Sciences, University of Milano, Italy
| | - Tung Gia Phan
- Blood Systems Research Institute, San Francisco, CA 94118, USA; Department of Laboratory Medicine, University of California at San Francisco, San Francisco, CA 94118, USA
| | - Eric Delwart
- Blood Systems Research Institute, San Francisco, CA 94118, USA; Department of Laboratory Medicine, University of California at San Francisco, San Francisco, CA 94118, USA
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Predictors of survival and functional outcomes in natalizumab-associated progressive multifocal leukoencephalopathy. J Neurovirol 2015; 21:637-44. [PMID: 25771865 PMCID: PMC4628054 DOI: 10.1007/s13365-015-0316-4] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Revised: 12/19/2014] [Accepted: 01/09/2015] [Indexed: 01/21/2023]
Abstract
Natalizumab, a highly effective therapy for relapsing-remitting multiple sclerosis, is associated with a risk of progressive multifocal leukoencephalopathy (PML). The objective of this analysis was to examine factors predicting survival in a large natalizumab-associated PML global population. Patients with natalizumab-associated PML identified through postmarketing surveillance were followed up for up to 24 months using a structured questionnaire completed by treating physicians. Demographic and clinical characteristics, JC viral load, magnetic resonance imaging (MRI) results, and Expanded Disability Status Scale (EDSS) and Karnofsky Performance Scale (KPS) scores were compared in survivors and nonsurvivors. Kaplan-Meier analysis was used to model survival function. Among the 336 patients included in this analysis, 76 % survived, with mean follow-up time from PML diagnosis of 16.1 months for survivors; mean time from diagnosis to death was 4.7 months for nonsurvivors. Survivors were significantly younger at diagnosis, had significantly lower EDSS scores and higher KPS scores prior to PML diagnosis, and had significantly lower cerebrospinal fluid JC viral load at the time of diagnosis. Patients with less extensive disease on MRI at diagnosis had a higher survival rate than those with widespread disease. Survivors generally had less functional disability pre-PML, at PML diagnosis, and in subsequent months. In survivors, functional disability appeared to stabilize approximately 6 months post-PML diagnosis. In this analysis, younger age at diagnosis, less functional disability prior to PML diagnosis, lower JC viral load at diagnosis, and more localized brain involvement by MRI at the time of diagnosis appeared to predict improved survival in natalizumab-associated PML.
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JC virus quasispecies analysis reveals a complex viral population underlying progressive multifocal leukoencephalopathy and supports viral dissemination via the hematogenous route. J Virol 2014; 89:1340-7. [PMID: 25392214 DOI: 10.1128/jvi.02565-14] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
UNLABELLED Opportunistic infection of oligodendrocytes by human JC polyomavirus may result in the development of progressive multifocal encephalopathy in immunocompromised individuals. Neurotropic JC virus generally harbors reorganized noncoding control region (NCCR) DNA interspersed on the viral genome between early and late coding genes. By applying 454 sequencing on NCCR DNA amplified from body fluid samples (urine, plasma, and cerebrospinal fluid [CSF]) from 19 progressive multifocal leukoencephalopathy (PML) patients, we attempted to reveal the composition of the JC polyomavirus population (the quasispecies, i.e., the whole of the consensus population and minor viral variants) contained in different body compartments and to better understand intrapatient viral dissemination. Our data demonstrate that in the CSF of PML patients, the JC viral population is often a complex mixture composed of multiple viral variants that contribute to the quasispecies. In contrast, urinary JC virus highly resembled the archetype virus, and urine most often did not contain minor viral variants. It also appeared that archetype JC virus could sporadically be identified in PML patient brain, although selection of rearranged JC virus DNA was favored. Comparison of the quasispecies from different body compartments within a given patient suggested a strong correlation between the viral population in plasma and CSF, whereas the viral population shed in urine appeared to be unrelated. In conclusion, it is shown that the representation of viral DNA in the CSF following the high-level DNA replication in the brain underlying PML has hitherto been much underestimated. Our data also underscore that the hematogenous route might play a pivotal role in viral dissemination from or toward the brain. IMPORTANCE For the first time, the JC polyomavirus population contained in different body compartments of patients diagnosed with progressive multifocal encephalopathy has been studied by deep sequencing. Two main findings came out of this work. First, it became apparent that the complexity of the viral population associated with PML has been highly underestimated so far, suggestive of a highly dynamic process of reorganization of the noncoding control region of JC polyomavirus in vivo, mainly in CSF and blood. Second, evidence showing viral dissemination from and/or toward the brain via the hematogenous route was provided, confirming a hypothesis that was recently put forward in the field.
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Ohara H, Kataoka H, Nakamichi K, Saijo M, Ueno S. Favorable outcome after withdrawal of immunosuppressant therapy in progressive multifocal leukoencephalopathy after renal transplantation: Case report and literature review. J Neurol Sci 2014; 341:144-6. [DOI: 10.1016/j.jns.2014.03.048] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 02/20/2014] [Accepted: 03/25/2014] [Indexed: 02/03/2023]
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Giacomini PS, Rozenberg A, Metz I, Araujo D, Arbour N, Bar-Or A. Maraviroc and JC virus-associated immune reconstitution inflammatory syndrome. N Engl J Med 2014; 370:486-8. [PMID: 24476450 PMCID: PMC5052063 DOI: 10.1056/nejmc1304828] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Nakamichi K, Tajima S, Lim CK, Saijo M. High-resolution melting analysis for mutation scanning in the non-coding control region of JC polyomavirus from patients with progressive multifocal leukoencephalopathy. Arch Virol 2014; 159:1687-96. [PMID: 24463953 DOI: 10.1007/s00705-014-1988-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Accepted: 01/12/2014] [Indexed: 11/29/2022]
Abstract
JC polyomavirus (JCV) is the causative agent of progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease. JCV isolates from PML patients have hypervariable mutations in the noncoding control region (NCCR) of the viral genome. Although nucleotide sequencing analysis of NCCR mutation is useful for the confirmation of PML diagnosis and basic studies examining JCV variants, it is often labor-intensive, time-consuming, and expensive. This study was conducted to evaluate the feasibility of a high-resolution melting (HRM) analysis technique for the rapid and low-cost scanning of NCCR mutations. The real-time PCR-HRM assay was developed with a pair of primers targeting the NCCR, and mutational patterns of NCCRs were compared using sequence-confirmed JCV DNA clones and CSF DNAs from PML patients. The NCCR patterns of DNA clones of the archetype JCV and PML-type variants could be differentiated by PCR-HRM. The mutational patterns of the rearranged NCCR clones were similar to those of JCV variants in the original CSF specimens as judged by nested PCR-HRM using pre-amplified targets. In addition, nested PCR-HRM could distinguish NCCR mutations in the JCV DNAs from each specimen at the patient level. These results indicate that the HRM-based assay affords a valuable technique for PML diagnosis and a versatile tool for the rapid scanning of NCCR mutations.
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Affiliation(s)
- Kazuo Nakamichi
- Department of Virology 1, National Institute of Infectious Diseases, Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan,
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Comar M, Zanotta N, Del Savio R, Vascotto F, Calabrese N, Zorat F, Pozzato G. No evidence of Polyomavirus and EBV infections in Italian patients with mixed cryoglobulinemia infected chronically with HCV. J Med Virol 2013; 86:666-71. [DOI: 10.1002/jmv.23867] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/24/2013] [Indexed: 12/31/2022]
Affiliation(s)
- Manola Comar
- Institute for Maternal and Child Health-IRCCS “Burlo Garofolo,”; Trieste Italy
- Department of Medical Sciences Clinical Unit of Hygiene; University of Trieste; Trieste Italy
| | - Nunzia Zanotta
- Institute for Maternal and Child Health-IRCCS “Burlo Garofolo,”; Trieste Italy
| | - Rossella Del Savio
- Institute for Maternal and Child Health-IRCCS “Burlo Garofolo,”; Trieste Italy
| | - Fulvia Vascotto
- Institute for Maternal and Child Health-IRCCS “Burlo Garofolo,”; Trieste Italy
| | - Nadia Calabrese
- Department of Medical Sciences Clinical Unit of Haematology; University of Trieste; Trieste Italy
| | - Francesca Zorat
- Department of Medical Sciences Clinical Unit of Haematology; University of Trieste; Trieste Italy
| | - Gabriele Pozzato
- Department of Medical Sciences Clinical Unit of Haematology; University of Trieste; Trieste Italy
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Beltrami S, Gordon J. Immune surveillance and response to JC virus infection and PML. J Neurovirol 2013; 20:137-49. [PMID: 24297501 DOI: 10.1007/s13365-013-0222-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Revised: 11/06/2013] [Accepted: 11/13/2013] [Indexed: 01/16/2023]
Abstract
The ubiquitous human polyomavirus JC virus (JCV) is the established etiological agent of the debilitating and often fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). Most healthy individuals have been infected with JCV and generate an immune response to the virus, yet remain persistently infected at subclinical levels. The onset of PML is rare in the general population, but has become an increasing concern in immunocompromised patients, where reactivation of JCV leads to uncontrolled replication in the CNS. Understanding viral persistence and the normal immune response to JCV provides insight into the circumstances which could lead to viral resurgence. Further, clues on the potential mechanisms of reactivation may be gleaned from the crosstalk among JCV and HIV-1, as well as the impact of monoclonal antibody therapies used for the treatment of autoimmune disorders, including multiple sclerosis, on the development of PML. In this review, we will discuss what is known about viral persistence and the immune response to JCV replication in immunocompromised individuals to elucidate the deficiencies in viral containment that permit viral reactivation and spread.
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Affiliation(s)
- Sarah Beltrami
- Department of Neuroscience and Center for Neurovirology, Temple University School of Medicine, 3500 North Broad Street, Philadelphia, PA, 19140, USA
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Clifford DB, Nath A, Cinque P, Brew BJ, Zivadinov R, Gorelik L, Zhao Z, Duda P. A study of mefloquine treatment for progressive multifocal leukoencephalopathy: results and exploration of predictors of PML outcomes. J Neurovirol 2013; 19:351-8. [PMID: 23733308 PMCID: PMC3758507 DOI: 10.1007/s13365-013-0173-y] [Citation(s) in RCA: 114] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2013] [Revised: 05/03/2013] [Accepted: 05/07/2013] [Indexed: 12/02/2022]
Abstract
Immune reconstitution has improved outcomes for progressive multifocal leukoencephalopathy (PML), a potentially lethal brain disease caused by JC virus (JCV). However, an antiviral treatment to control JCV is needed when immune reconstitution is delayed or not possible. On the basis of in vitro efficacy, this study evaluated the effect of mefloquine on PML and factors that may predict PML outcomes. This 38-week, open-label, randomized, parallel-group, proof-of-concept study compared patients with PML who received standard of care (SOC) with those who received SOC plus mefloquine (250 mg for 3 days, then 250 mg weekly). Patients randomized to SOC could add mefloquine treatment at week 4. The primary endpoint was change from baseline to weeks 4 and 8 in JCV DNA copy number (load) in cerebrospinal fluid (CSF). Exploratory analyses evaluated factors that might correlate with clinical outcome. The majority of enrolled patients were HIV positive. Preplanned interim data analyses suggested that the study was unlikely to successfully demonstrate a significant difference between groups; therefore, the study was terminated prematurely. There was no significant difference between groups in CSF JCV DNA loads or clinical/MRI findings. Decrease in CSF JCV DNA load from baseline to week 4 was associated with a better clinical outcome at 16 weeks, as measured by Karnofsky scores. This study found no evidence of anti-JCV activity by mefloquine. An early decrease of CSF JCV DNA load appears to be associated with a better clinical outcome.
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Affiliation(s)
- David B Clifford
- Department of Neurology, Washington University in St. Louis, Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
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Nakamichi K, Kishida S, Tanaka K, Suganuma A, Sano Y, Sano H, Kanda T, Maeda N, Kira JI, Itoh A, Kato N, Tomimoto H, Kurane I, Lim CK, Mizusawa H, Saijo M. Sequential changes in the non-coding control region sequences of JC polyomaviruses from the cerebrospinal fluid of patients with progressive multifocal leukoencephalopathy. Arch Virol 2012; 158:639-50. [PMID: 23138154 DOI: 10.1007/s00705-012-1532-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2012] [Accepted: 10/01/2012] [Indexed: 11/28/2022]
Abstract
Progressive multifocal leukoencephalopathy (PML) is caused by JC polyomavirus (JCV) infection in the brain. JCV isolates from PML patients have variable mutations in the non-coding control region (NCCR) of the genome. This study was conducted to examine sequential changes in NCCR patterns of JCV isolates obtained from the cerebrospinal fluid (CSF) of PML patients. CSF specimens were collected from PML patients at different time points, the NCCR sequences were determined, and their compositions were assessed by computer-based analysis. In patients showing a marked increase in JCV load, the most frequent NCCR sequences in the follow-up specimens were different from those in the initial samples. In contrast, the dominant NCCRs in the CSF remained unaltered during the follow-up of individuals in whom the viral load decreased after therapeutic intervention. These data demonstrate that the majority of JCV variants emerge with the progression of PML and that these changes are suppressed when the viral load is decreased.
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Affiliation(s)
- Kazuo Nakamichi
- Department of Virology 1, National Institute of Infectious Diseases, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
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Gheuens S, Wüthrich C, Koralnik IJ. Progressive multifocal leukoencephalopathy: why gray and white matter. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2012; 8:189-215. [PMID: 23092189 DOI: 10.1146/annurev-pathol-020712-164018] [Citation(s) in RCA: 97] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Since it was first described in 1958, progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the brain caused by the polyomavirus JC (JCV), has evolved tremendously. It was once considered a noninflammatory disease that affected exclusively oligodendrocytes and astrocytes in the white matter of immunosuppressed individuals and was almost always fatal. Today, we understand that PML can present during the course of an immune reconstitution inflammatory syndrome and that it affects a broader range of individuals, including patients with minimal immunosuppression and those who are treated with novel immunomodulatory medications. Furthermore, JCV-infected glial cells are frequently located at the gray matter-white matter junction or within the gray matter, causing demyelinating lesions within cortical areas. Finally, JCV variants can also infect neurons, leading to the recognition of two distinct clinical entities: JCV granule cell neuronopathy and JCV encephalopathy.
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Affiliation(s)
- Sarah Gheuens
- Division of Neurovirology and Departments of Neurology and Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
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Specific protein profile in cerebrospinal fluid from HIV-1-positive cART-treated patients affected by neurological disorders. J Neurovirol 2012; 18:416-22. [DOI: 10.1007/s13365-012-0109-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Revised: 04/19/2012] [Accepted: 04/26/2012] [Indexed: 12/23/2022]
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