RESUMO
Introduction: Progressive Multifocal Leukoencephalopathy (PML) is a rare and deadly demyelinating disease caused by JC virus (JCV) replication in the central nervous system. PML occurs exclusively in patients with severe underlying immune deficiencies, including AIDS and hematological malignancies. PML has also emerged as a significant threat to patients on potent new immunosuppressive biologics, including natalizumab in multiple sclerosis. Methods: Here, we developed an IFN-γ release assay (IGRA) that mainly detects JCV-specific effector memory T cells and effectors T cells in the blood. Results: This assay was frequently positive in patients with active PML (with a positive JCV PCR in CSF) of various underlying immunosuppression causes (84% sensitivity). Only 3% of healthy donors had a positive response (97% specificity). The frequency of positivity also increased in multiple sclerosis patients according to the time on natalizumab (up to 36% in patients treated for more than 48 months, who are considered at a higher risk of PML). Discussion: The results show this assay's frequent or increased positivity in patients with PML or an increased risk of PML, respectively. The assay may help to stratify the risk of PML.
Assuntos
Interferon gama , Vírus JC , Leucoencefalopatia Multifocal Progressiva , Células T de Memória , Humanos , Leucoencefalopatia Multifocal Progressiva/imunologia , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Leucoencefalopatia Multifocal Progressiva/etiologia , Masculino , Vírus JC/imunologia , Feminino , Pessoa de Meia-Idade , Adulto , Células T de Memória/imunologia , Células T de Memória/metabolismo , Natalizumab/uso terapêutico , Idoso , Esclerose Múltipla/imunologia , Esclerose Múltipla/tratamento farmacológicoRESUMO
INTRODUCTION: One strategy to mitigate progressive multifocal leukoencephalopathy (PML) risk is to switch to other highly effective disease-modifying therapies (DMTs). However, the optimal switch DMT following natalizumab (NTZ) discontinuation is yet to be determined. OBJECTIVE: The objective of the study is to determine the most effective and tolerable DMTs to switch to following NTZ discontinuation due to John Cunningham virus (JCV) antibody positivity. METHODS: This is a multicenter observational cohort study that included all stable relapsing-remitting multiple sclerosis (MS) patients who were treated with NTZ for at least 6 months before switching therapy due to JCV antibody positivity. RESULTS: Of 321 patients, 255 switched from NTZ to rituximab/ocrelizumab, 52 to fingolimod, and 14 to alemtuzumab, with higher annualized relapse rate (ARR) in fingolimod switchers (0.193) compared with rituximab/ocrelizumab or alemtuzumab (0.028 and 0.032, respectively). Fingolimod switchers also had increased disability progression (p = 0.014) and a higher proportion developed magnetic resonance imaging (MRI) lesions compared with rituximab/ocrelizumab (62.9% vs. 13.0%, p < 0.001, and 66.6% vs. 24.0%, p < 0.001, respectively). Mean drug survival favored rituximab/ocrelizumab or alemtuzumab over fingolimod (p < 0.001). CONCLUSION: Our study shows superior effectiveness of rituximab/ocrelizumab and alemtuzumab compared with fingolimod in stable patients switching from NTZ due to JC virus antibody positivity.
Assuntos
Fatores Imunológicos , Vírus JC , Leucoencefalopatia Multifocal Progressiva , Esclerose Múltipla Recidivante-Remitente , Natalizumab , Humanos , Natalizumab/uso terapêutico , Natalizumab/efeitos adversos , Feminino , Adulto , Masculino , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Fatores Imunológicos/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Vírus JC/imunologia , Pessoa de Meia-Idade , Substituição de Medicamentos , Rituximab/efeitos adversos , Rituximab/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Cloridrato de Fingolimode/uso terapêutico , Alemtuzumab/efeitos adversos , Alemtuzumab/uso terapêuticoRESUMO
INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) is a potentially life-threatening complication among Multiple Sclerosis (MS) patients under natalizumab treatment, with serum anti-JCV antibody titers being used for stratification risk. Given the critical role of interferon (IFN)/B-cell activating factor (BAFF) axis in humoral immune responses against viruses, we explored whether it is involved in the generation of serum anti-JCV antibodies among these patients. METHODS: 162 consecutive patients with relapsing-remitting MS under natalizumab treatment were included. Serum anti-JCV antibodies were measured at baseline, as well as 12 and 24 months after treatment initiation. Type I and II IFN-inducible genes and BAFF expression were quantitated in peripheral blood by qRT-PCR. Moreover, BAFF rs9514828, rs1041569, and rs9514827 gene variants were assessed by RFLP-PCR. RESULTS: While type I and II IFN inducible gene expression were not associated with anti-JCV serum titers, the latter were significantly correlated with BAFF gene expression. Of interest, the TTT haplotype of the studied BAFF variants was more frequently detected in male, but not female anti-JCV (+) MS patients compared to anti-JCV (-) counterparts at baseline, as well as at 12 months and 24 months of natalizumab treatment. Measures of clinical validity/utility for the BAFF TTT haplotype showed 88% specificity, 45%, positive predictive value, and sensitivity of 70% for the discrimination of anti-JCV (+) male MS patients after 24 months of treatment. CONCLUSIONS: Our study suggests an implication of the BAFF axis in the production of serum anti-JCV antibodies. Additionally, the BAFF TTT haplotype derived from the rs9514828, rs1041569, and rs9514827 variants may represent a novel risk factor for anti-JCV seropositivity and indirectly for PML development among male MS patients treated with natalizumab.
Assuntos
Fator Ativador de Células B , Fatores Imunológicos , Vírus JC , Leucoencefalopatia Multifocal Progressiva , Natalizumab , Humanos , Natalizumab/uso terapêutico , Fator Ativador de Células B/sangue , Fator Ativador de Células B/genética , Masculino , Leucoencefalopatia Multifocal Progressiva/sangue , Leucoencefalopatia Multifocal Progressiva/genética , Adulto , Feminino , Fatores Imunológicos/uso terapêutico , Vírus JC/imunologia , Vírus JC/genética , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/genética , Esclerose Múltipla Recidivante-Remitente/imunologia , Pessoa de Meia-Idade , Anticorpos Antivirais/sangue , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Natalizumab is an effective treatment for relapsing multiple sclerosis (MS). During therapy, individuals are at increased risk of developing progressive multifocal leukoencephalopathy (PML). So far, the relevant reservoir for PML-type JC polyomavirus (JCV) remains elusive. We here tested if the detection of JCV-DNA in stool of persons with MS treated with natalizumab could be a future tool for PML risk assessment. METHODS: The presence of JCV-DNA in stool, urine, and whole blood of MS patients treated with natalizumab and known serum anti-JCV antibodies index values (IV) was studied. Different DNA extraction methods, real-time (RT) and droplet digital (dd) PCR techniques were compared. JCV isolates were screened for PML-associated variants by sequencing. RESULTS: Thirty MS patients treated with natalizumab were screened. For 21 patients, blood, stool, and urine samples were available. These patients were stratified according to their serum anti-JCV antibody IV (high (>1.5, n = 12); medium (1.5-0.9, n = 2); low (<0.9, n = 1); negative (n = 6)). JCV-DNA could not be detected in the whole blood or stool samples. Four urine samples had measurable JCV-DNA, ranging from 1.71×104-1.07×108 international units (IU)/mL detected by RT-PCR, corresponding to 4.62×104-9.85×106 copies/mL measured by ddPCR. All JCV variants were wild-type and derived from patients with high antibody IV. CONCLUSION: Stool-specific DNA extraction methods provided the highest quality of DNA, while the sensitivity of ddPCR and RT- PCR was comparable. Our findings do not support assessing stool samples for PML risk stratification in persons with MS. Further studies are needed to explore where PML-associated viral variants arise.
Assuntos
Anticorpos Antivirais , DNA Viral , Fezes , Fatores Imunológicos , Vírus JC , Natalizumab , Humanos , Vírus JC/isolamento & purificação , Vírus JC/imunologia , Natalizumab/uso terapêutico , Fezes/virologia , Adulto , Masculino , Feminino , Anticorpos Antivirais/sangue , DNA Viral/sangue , DNA Viral/análise , Pessoa de Meia-Idade , Leucoencefalopatia Multifocal Progressiva/sangue , Leucoencefalopatia Multifocal Progressiva/virologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/virologia , Esclerose Múltipla/sangueRESUMO
PURPOSE: This study aimed to investigate the prevalence and viral reactivations of clinical interest in the immunocompromised patient with particular focus on hematologic and solid organ transplant recipients. METHODS: Molecular screening data of CMV, EBV, JCV and BKV from 2011 to 2023 were analyzed. This extensive time span allowed the access to more than 100,000 samples from over 20,000 patients treated at Policlinico Umberto I. It was possible to temporally investigate patient attendance patterns, average age distribution, seasonality of infections, and positivity rates of the analyzed viruses. RESULTS: Between 2019 and 2022 a significant reduction in organ transplants performed and in the positive molecular detection of EBV, JCV and BKV was observed. Additionally, there has been a noteworthy decrease in CMV reactivations, with a reduction of up to 50% starting in 2019. A remarkable reduction of 39% in the rate of CMV viral reactivation has been also achieved in SOT between 2016 and 2023. CONCLUSION: The years following 2019 were profoundly impacted by the COVID-19 pandemic era. This period resulted in a substantial reduction in healthcare services and hospital visits. Furthermore, the introduction of the drug Letermovir in Italy in 2019 demonstrated remarkable efficacy, evidenced by a reduction in CMV reactivations. Additionally, the adoption of a novel clinical approach centered on personalized therapy facilitated improved management of immunocompromised patients.
Assuntos
Hospitais Universitários , Hospedeiro Imunocomprometido , Humanos , Itália/epidemiologia , Hospitais Universitários/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , COVID-19/epidemiologia , COVID-19/virologia , Feminino , Ativação Viral , Viroses/epidemiologia , Viroses/virologia , Idoso , Adulto , Vírus JC/genética , Vírus JC/isolamento & purificação , Vírus JC/imunologia , Vírus BK/genética , Vírus BK/isolamento & purificação , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/tratamento farmacológico , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/imunologia , Prevalência , Transplante de Órgãos/efeitos adversos , Transplantados/estatística & dados numéricos , Citomegalovirus/genética , Citomegalovirus/imunologia , Infecções por Polyomavirus/epidemiologia , Infecções por Polyomavirus/virologiaAssuntos
Anticorpos Antivirais , Vírus JC , Leucoencefalopatia Multifocal Progressiva , Esclerose Múltipla , Natalizumab , Humanos , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Leucoencefalopatia Multifocal Progressiva/etiologia , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Leucoencefalopatia Multifocal Progressiva/imunologia , Natalizumab/efeitos adversos , Natalizumab/uso terapêutico , Vírus JC/imunologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/complicações , Evolução Fatal , Anticorpos Antivirais/sangue , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/uso terapêutico , Feminino , Adulto , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/complicações , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic offered an epidemiological opportunity to evaluate if isolation and masking affected John Cunningham (JC) virus transmission. OBJECTIVE: This study aimed to assess the proportion of natalizumab-treated patients who converted to a positive anti-JCV antibody serostatus before and during the pandemic. METHODS: Data from TYSABRI Outreach: Unified Commitment to Health (TOUCH) for 22,375 US patients treated with natalizumab with anti-JCV antibody records were assessed in epochs annually from 2017 to 2022. RESULTS: Pre-pandemic anti-JCV antibody serostatus change was observed for 7.4%-7.7%. During the first and second years of the pandemic, 7.3% and 7.2% of patients' serostatus changed, respectively. CONCLUSION: The proportion of patients with anti-JCV antibody serostatus change did not significantly differ during the first 2 years of the pandemic compared with prior years. In contrast to seasonal influenza, masking and social distancing had no discernable effect on JCV serostatus change.
Assuntos
Anticorpos Antivirais , COVID-19 , Vírus JC , Esclerose Múltipla , Distanciamento Físico , Humanos , COVID-19/prevenção & controle , COVID-19/epidemiologia , COVID-19/imunologia , Esclerose Múltipla/imunologia , Esclerose Múltipla/tratamento farmacológico , Masculino , Feminino , Adulto , Anticorpos Antivirais/sangue , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , Vírus JC/imunologia , Natalizumab/uso terapêutico , SARS-CoV-2/imunologia , Fatores Imunológicos/uso terapêuticoRESUMO
Polyomavirus JC (JCPyV) causes the demyelinating disease progressive multifocal leukoencephalopathy (PML). JCPyV infection is very common in childhood and, under conditions of severe immunosuppression, JCPyV may reactivate to cause PML. JC viral proteins expression is regulated by the JCPyV non-coding control region (NCCR), which contains binding sites for cellular transcriptional factors which regulate JCPyV transcription. Our earlier studies suggest that JCPyV reactivation occurs within glial cells due to cytokines such as TNF-α which stimulate viral gene expression. In this study, we examined interferon-α (IFNα) or ß (IFNß) which have a negative effect on JCPyV transcriptional regulation. We also showed that these interferons induce the endogenous liver inhibitory protein (LIP), an isoform of CAAT/enhancer binding protein beta (C/EBPß). Treatment of glial cell line with interferons increases the endogenous level of C/EBPß-LIP. Furthermore, we showed that the negative regulatory role of the interferons in JCPyV early and late transcription and viral replication is more pronounced in the presence of C/EBPß-LIP. Knockdown of C/EBPß-LIP by shRNA reverse the inhibitory effect on JCPyV viral replication. Therefore, IFNα and IFNß negatively regulate JCPyV through induction of C/EBPß-LIP, which together with other cellular transcriptional factors may control the balance between JCPyV latency and activation.
Assuntos
Interferon-alfa/metabolismo , Interferon beta/metabolismo , Vírus JC/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Linhagem Celular Tumoral , DNA Viral/genética , Expressão Gênica/genética , Regulação Viral da Expressão Gênica/genética , Humanos , Interferon-alfa/imunologia , Interferon beta/imunologia , Vírus JC/genética , Vírus JC/imunologia , Vírus JC/patogenicidade , Leucoencefalopatia Multifocal Progressiva/virologia , Neuroglia , Isoformas de Proteínas , Replicação Viral/genéticaRESUMO
BACKGROUND: Progressive multifocal leukoencephalopathy, a rare disease of the CNS caused by JC virus and occurring in immunosuppressed people, is typically fatal unless adaptive immunity is restored. JC virus is a member of the human polyomavirus family and is closely related to the BK virus. We hypothesised that use of partly HLA-matched donor-derived BK virus-specific T cells for immunotherapy in progressive multifocal leukoencephalopathy would be feasible and safe. METHODS: We did an open-label, single-cohort pilot study in patients (aged 18 years or older) with clinically definite progressive multifocal leukoencephalopathy and disease progression in the previous month at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA). Overlapping peptide libraries derived from large T antigen and major capsid protein VP1 of BK virus with high sequence homology to JC virus counterparts were used to generate polyomavirus-specific T cells cross-recognising JC virus antigens. Polyomavirus-specific T cells were manufactured from peripheral blood mononuclear cells of first-degree relative donors aged 18 years or older. These cells were administered to patients by intravenous infusion at 1â×â106 polyomavirus-specific T cells per kg, followed by up to two additional infusions at 2â×â106 polyomavirus-specific T cells per kg. The primary endpoints were feasibility (no manufacturing failure based on meeting release criteria, achieving adequate numbers of cell product for clinical use, and showing measurable antiviral activity) and safety in all patients. The safety monitoring period was 28 days after each infusion. Patients were followed up with serial MRI for up to 12 months after the final infusion. This trial is registered at ClinicalTrials.gov, NCT02694783. FINDINGS: Between April 7, 2016, and Oct 19, 2018, 26 patients were screened, of whom 12 were confirmed eligible and received treatment derived from 14 matched donors. All administered polyomavirus-specific T cells met the release criteria and recognised cognate antigens in vitro. 12 patients received at least one infusion, ten received at least two, and seven received a total of three infusions. The median on-study follow-up was 109·5 days (range 23-699). All infusions were tolerated well, and no serious treatment-related adverse events were observed. Seven patients survived progressive multifocal leukoencephalopathy for longer than 1 year after the first infusion, whereas five died of progressive multifocal leukoencephalopathy within 3 months. INTERPRETATION: We showed that generation of polyomavirus-specific T cells from healthy related donors is feasible, and these cells can be safely used as an infusion for adoptive immunotherapy of progressive multifocal leukoencephalopathy. Although not powered to assess efficacy, our data provide additional support for this strategy as a potential life-saving therapy for some patients. FUNDING: Intramural Research Program of the National Institute of Neurological Disorders and Stroke of the NIH.
Assuntos
Vírus BK/imunologia , Imunoterapia/métodos , Leucoencefalopatia Multifocal Progressiva/terapia , Linfócitos T/imunologia , Adulto , Idoso , Doadores de Sangue , Estudos de Coortes , Determinação de Ponto Final , Estudos de Viabilidade , Feminino , Humanos , Imunoterapia/efeitos adversos , Vírus JC/imunologia , Leucoencefalopatia Multifocal Progressiva/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Projetos Piloto , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Background: Many investigations reported the association between human tumors and JCPyV, a polyomavirus with oncogenic potential. The association has been supported by studies that found JCPyV footprints in CRC and gliomas of different types. Indeed, JCPyV footprints including its nucleic acids and Tag oncoprotein have been revealed in CRC tissues. Methods: Herein, sera from colorectal carcinoma (CRC) affected patients and healthy individuals (HS), employed as control, were analysed for immunoglobulin G (IgG) antibodies against specific JCPyV viral capsid protein 1 (VP1) antigens. The investigation was carried out employing an innovative immunological assay. Indeed, an indirect enzyme-linked immunosorbent assay (ELISA) with JCPyV VP1 mimotopes was used. JCPyV VP1 mimotopes consisted of synthetic peptides mimicking VP1 epitopes. Results: Sera from CRC affected patients, evaluated using indirect ELISAs with synthetic mimotopes, showed a significant lower prevalence of IgG antibodies against JCPyV VP1 mimotopes (26%) compared to HS (51%), p<0.005. These data were confirmed by another method, the hemagglutination inhibition (HAI) assay. Altogether these results, i.e. the prevalence of serum IgG antibodies against JCPyV VP1 mimotopes from patients with CRC is approximately 50% lower than in HS, are of interest. Discussion: Our data suggest that patients with CRC are significantly poor responders against JCPyV VP1 antigens. It is possible that CRC patients are affected by a specific immunological deregulation. This immunological dysfunction, revelled in CRC patients, may account for their predisposition to the colorectal carcinoma onset.
Assuntos
Neoplasias Colorretais/epidemiologia , Vírus JC/isolamento & purificação , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Proteínas do Capsídeo/imunologia , Neoplasias Colorretais/sangue , Neoplasias Colorretais/virologia , Ensaio de Imunoadsorção Enzimática , Epitopos/imunologia , Feminino , Testes de Inibição da Hemaglutinação , Humanos , Imunoglobulina G/sangue , Vírus JC/imunologia , Masculino , Pessoa de Meia-Idade , PrevalênciaRESUMO
JC polyomavirus (JCV), a DNA virus that leads to persistent infection in humans, is the causative agent of progressive multifocal leukoencephalopathy, a lethal brain disease that affects immunocompromised individuals. Almost nothing is currently known about how JCV infection is controlled by the innate immune response and, further, whether JCV has evolved mechanisms to antagonize antiviral immunity. Here, we show that the innate immune sensors retinoic acid-inducible gene I (RIG-I) and cGMP-AMP synthase (cGAS) control JCV replication in human astrocytes. We further identify that the small t antigen (tAg) of JCV functions as an interferon (IFN) antagonist by suppressing RIG-I-mediated signal transduction. JCV tAg interacts with the E3 ubiquitin ligase TRIM25, thereby preventing its ability to bind RNA and to induce the K63-linked ubiquitination of RIG-I, which is known to facilitate RIG-I-mediated cytokine responses. Antagonism of RIG-I K63-linked ubiquitination and antiviral signaling is also conserved in the tAg of the related polyomavirus BK virus (BKV). These findings highlight how JCV and BKV manipulate a key innate surveillance pathway, which may stimulate research into designing novel therapies.IMPORTANCE The innate immune response is the first line of defense against viral pathogens, and in turn, many viruses have evolved strategies to evade detection by the host's innate immune surveillance machinery. Investigation of the interplay between viruses and the innate immune response provides valuable insight into potential therapeutic targets against viral infectious diseases. JC polyomavirus (JCV) is associated with a lifelong, persistent infection that can cause a rare neurodegenerative disease, called progressive multifocal leukoencephalopathy, in individuals that are immunosuppressed. The molecular mechanisms of JCV infection and persistence are not well understood, and very little is currently known about the relevance of innate immunity for the control of JCV replication. Here, we define the intracellular innate immune sensors responsible for controlling JCV infection and also demonstrate a novel mechanism by which a JCV-encoded protein acts as an antagonist of the type I interferon-mediated innate immune response.
Assuntos
Antígenos Virais de Tumores/imunologia , Proteína DEAD-box 58/imunologia , Imunidade Inata , Vírus JC/imunologia , Proteínas de Ligação a RNA/antagonistas & inibidores , RNA/metabolismo , Receptores Imunológicos/imunologia , Fatores de Transcrição/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Antígenos Virais de Tumores/genética , Astrócitos/virologia , Células Cultivadas , Proteína DEAD-box 58/genética , Proteína DEAD-box 58/metabolismo , Células HEK293 , Humanos , Vírus JC/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Fatores de Transcrição/genética , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
Progressive multifocal leukoencephalopathy (PML) is attributed to reactivation of the John Cunningham virus (JCV), in the central nervous system as a result of immunosuppression. Low L-selectin (CD62L) expression on cryopreserved T-cells has been advocated as a biomarker for natalizumab related PML in patients with Relapsing-Remitting Multiple Sclerosis. A rare case of PML in an elderly patient without known factors of immunosuppression or immunomodulation is hereby presented. T-cell L-selectin expression levels and serum anti-JCV antibody index were evaluated in order to explore mechanistic insight to the pathways that presumably contribute towards PML development in this rare clinical setting.
Assuntos
Selectina L/biossíntese , Leucoencefalopatia Multifocal Progressiva/imunologia , Linfócitos T/imunologia , Idoso , Biomarcadores/sangue , Biópsia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Feminino , Humanos , Imunocompetência , Imunossenescência/imunologia , Vírus JC/imunologia , Selectina L/sangue , Leucoencefalopatia Multifocal Progressiva/sangue , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Imageamento por Ressonância MagnéticaRESUMO
The use of Natalizumab in Multiple Sclerosis (MS) can cause the reactivation of the polyomavirus JC (JCPyV); this may result in the development of progressive multifocal leukoencephalopathy (PML), a rare and usually lethal disease. JCPyV infection is highly prevalent in worldwide population, but the detection of anti-JCPyV antibodies is not sufficient to identify JCPyV infection, as PML can develop even in patients with negative JCPyV serology. Better comprehension of the JCPyV biology could allow a better understanding of JCPyV infection and reactivation, possibly reducing the risk of developing PML. Here, we investigated whether JCPyV miR-J1-5p-a miRNA that down-regulates the early phase viral protein T-antigen and promotes viral latency-could be detected and quantified by digital droplet PCR (ddPCR) in urine of 25 Natalizumab-treated MS patients. A 24-month study was designed: baseline, before the first dose of Natalizumab, and after 1 (T1), 12 (T12) and 24 months (T24) of therapy. miR-J1-5p was detected in urine of 7/25 MS patients (28%); detection was possible in three cases at T24, in two cases at T12, in one case at T1 and T12, and in the last case at baseline and T1. Two of these patients were seronegative for JCPyV Ab, and viral DNA was never found in either urine or blood. To note, only in one case miR-J1-5p was detected before initiation of Natalizumab. These results suggest that the measurement of miR-J1-5p in urine, could be a biomarker to monitor JCPyV infection and to better identify the possible risk of developing PML in Natalizumab-treated MS patients.
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Vírus JC/crescimento & desenvolvimento , MicroRNAs/urina , Esclerose Múltipla/tratamento farmacológico , Natalizumab/uso terapêutico , Ativação Viral/efeitos dos fármacos , Anticorpos Antivirais/sangue , Antígenos Virais de Tumores/biossíntese , Biomarcadores/urina , Regulação para Baixo/genética , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Vírus JC/efeitos dos fármacos , Vírus JC/imunologia , Leucoencefalopatia Multifocal Progressiva/virologia , Masculino , MicroRNAs/genética , Latência Viral/genéticaAssuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Linfoma Folicular/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , DNA Viral/isolamento & purificação , Evolução Fatal , Feminino , Humanos , Hospedeiro Imunocomprometido , Vírus JC/genética , Vírus JC/imunologia , Vírus JC/isolamento & purificação , Leucoencefalopatia Multifocal Progressiva/sangue , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Leucoencefalopatia Multifocal Progressiva/imunologia , Linfoma Folicular/imunologia , Imageamento por Ressonância Magnética , Recidiva Local de Neoplasia/imunologiaRESUMO
Based on publicly available data, we reevaluated current algorithms for stratifying the risk of progressive multifocal leukoencephalopathy (PML) in natalizumab-treated patients with multiple sclerosis, and found that there are a number of issues. First and foremost, our analysis highlights the necessity of separate PML incidence assessments for the U.S. versus Europe, and indicates that the risk in John Cunningham virus (JCV) antibody-negative patients may be higher than previously communicated. Additionally, we advocate introducing a low-risk JCV index threshold of 0.45 for individuals with prior exposure to an immunosuppressant, and setting the low-risk threshold at 0.6 instead of 0.9 for those without such pretherapies. On the other hand, the risk of PML on natalizumab, in general, appears to not only plateau but to actually decrease after about 5 years of continuous dosing.
Assuntos
Anticorpos Antivirais/sangue , Fatores Imunológicos/efeitos adversos , Vírus JC/imunologia , Leucoencefalopatia Multifocal Progressiva , Esclerose Múltipla/tratamento farmacológico , Natalizumab/efeitos adversos , Medição de Risco/normas , Algoritmos , Canadá/epidemiologia , Europa (Continente)/epidemiologia , Humanos , Fatores Imunológicos/administração & dosagem , Leucoencefalopatia Multifocal Progressiva/sangue , Leucoencefalopatia Multifocal Progressiva/epidemiologia , Leucoencefalopatia Multifocal Progressiva/etiologia , Leucoencefalopatia Multifocal Progressiva/imunologia , Natalizumab/administração & dosagem , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: The vast majority of polyomavirus nephropathy (PVN) is due to BK virus, but rare cases result from JC virus reactivation. To date, only a handful of biopsy-proven JC-PVN cases have been reported. Here, we describe the clinical and pathologic findings in 7 patients with biopsy-proven JC-PVN. METHODS: Search of the pathology archives at 2 institutions found 7 cases of JC-PVN. Clinical data were extracted from the electronic medical records, and the biopsies were reviewed. RESULTS: Four cases were diagnosed at 6 y posttransplant or later. The remaining 3 cases presented within approximately 2 y posttransplant, of which 2 showed subclinical JC-PVN on surveillance biopsy. Two early presenting patients were treated for acute rejection just before acquiring JC-PVN. Late presenting patients had higher chronicity, which correlated to worse outcome. All but 1 biopsy showed nonspecific inflammation within areas of interstitial fibrosis without significant inflammation in unscarred cortex. The earliest presenting patient was the exception and showed active inflammation with tubulitis. Viral cytopathic changes were detected in all cases with moderate or high-histologic viral load (pvl), showing preference for the distal tubules and medulla. The 2 cases with low pvl did not demonstrate cytopathic changes but were SV40 positive. CONCLUSIONS: JC-PVN can be insidious in presentation, which may cause delayed or missed diagnosis. Unlike BK-PVN, which typically occurs early in the posttransplant period, JC-PVN can occur both early and late following transplant. Overreliance on negative plasma and urine BK viral loads to exclude PVN can be a pitfall.
Assuntos
Vírus JC/patogenicidade , Nefropatias/virologia , Transplante de Rim/efeitos adversos , Rim/virologia , Infecções por Polyomavirus/virologia , Infecções Tumorais por Vírus/virologia , Ativação Viral , Adulto , Idoso , Biópsia , California , Feminino , Fibrose , Interações Hospedeiro-Patógeno , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Vírus JC/imunologia , Rim/imunologia , Rim/patologia , Nefropatias/diagnóstico , Nefropatias/imunologia , Masculino , Pessoa de Meia-Idade , Infecções por Polyomavirus/diagnóstico , Infecções por Polyomavirus/imunologia , Fatores de Tempo , Resultado do Tratamento , Infecções Tumorais por Vírus/diagnóstico , Infecções Tumorais por Vírus/imunologia , Carga ViralRESUMO
JC virus (JCV) causes progressive multifocal leukoencephalopathy (PML) in immunosuppressed patients. There is currently no effective specific antiviral treatment and PML management relies on immune restoration. Prognosis markers are crucially needed in this disease because of its high mortality rate. In this work, we investigated the compartmentalization of JCV strains as well as the humoral neutralizing response in various matrices to further understand the pathophysiology of PML and define markers of survival. Four patients were included, of which three died in the few months following PML onset. Cerebrospinal fluid (CSF) viral loads were the highest, with plasma samples having lower viral loads and urine samples being mostly negative. Whether at PML onset or during follow-up, neutralizing antibody (NAb) titers directed against the same autologous strain (genotype or mutant) were the highest in plasma, with CSF titers being on average 430-fold lower and urine titers 500-fold lower at the same timepoint. Plasma NAb titers against autologous genotype or mutant were lower in non-survivor patients, though no neutralization "blind spot" was observed. The surviving patient was followed up until nine months after PML onset and presented, at that time, an increase in neutralizing titers, from 38-fold against the autologous genotype to around 200-fold against PML mutants. Our results suggest that patients' humoral neutralizing response against their autologous strain may play a role in PML outcome, with survivors developing high NAb titers in both plasma and CSF.
Assuntos
Interações Hospedeiro-Patógeno/imunologia , Imunidade Humoral , Vírus JC/imunologia , Leucoencefalopatia Multifocal Progressiva/imunologia , Leucoencefalopatia Multifocal Progressiva/patologia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Genótipo , Humanos , Vírus JC/genética , Leucoencefalopatia Multifocal Progressiva/mortalidade , Leucoencefalopatia Multifocal Progressiva/virologia , Mutação , Testes de Neutralização , Carga ViralRESUMO
Progressive Multifocal Leukoencephalopathy (PML) is a fatal demyelinating disease of the CNS, resulting from the lytic infection of oligodendrocytes by the human neurotropic polyomavirus JC (JCPyV), typically associated with severe immunocompromised states and, in recent years, with the use of immunotherapies. Apoptosis is a homeostatic mechanism to dispose of senescent or damaged cells, including virally infected cells, triggered in the vast majority of viral infections of the brain. Previously, we showed upregulation of the normally dormant anti-apoptotic protein Survivin in cases of PML, which-in vitro-resulted in protection from apoptosis in JCPyV-infected primary cultures of astrocytes and oligodendrocytes. In the present study, we first demonstrate the absence of apoptotic DNA fragmentation and the lack of caspase activity in 16 cases of PML. We also identified the viral protein large T-Antigen as being responsible for the activation of the Survivin promoter. Chromatin Immunoprecipitation assay shows a direct binding between T-Antigen and the Survivin promoter DNA. Finally, we have identified the specific region of T-Antigen, spanning from amino acids 266 and 688, which binds to Survivin and translocates it to the nucleus, providing evidence of a mechanism that results in the efficient replication of JCPyV and a potential target for novel therapies.
Assuntos
Antígenos Virais de Tumores/genética , Apoptose , Vírus JC/genética , Regiões Promotoras Genéticas , Survivina/genética , Adulto , Idoso , Animais , Antígenos Virais de Tumores/imunologia , Astrócitos/virologia , Caspases/imunologia , Linhagem Celular Tumoral , Células Cultivadas , Criança , Fragmentação do DNA , Feminino , Humanos , Vírus JC/imunologia , Vírus JC/patogenicidade , Leucoencefalopatia Multifocal Progressiva , Masculino , Camundongos , Pessoa de Meia-Idade , Oligodendroglia/virologia , Inclusão em Parafina , Survivina/imunologiaRESUMO
Polyomaviruses are ubiquitous human pathogens that cause lifelong, asymptomatic infections in healthy individuals. Although these viruses are restrained by an intact immune system, immunocompromised individuals are at risk for developing severe diseases driven by resurgent viral replication. In particular, loss of immune control over JC polyomavirus can lead to the development of the demyelinating brain disease progressive multifocal leukoencephalopathy (PML). Viral isolates from PML patients frequently carry point mutations in the major capsid protein, VP1, which mediates virion binding to cellular glycan receptors. Because polyomaviruses are non-enveloped, VP1 is also the target of the host's neutralizing antibody response. Thus, VP1 mutations could affect tropism and/or recognition by polyomavirus-specific antibodies. How these mutations predispose susceptible individuals to PML and other JCPyV-associated CNS diseases remains to be fully elucidated. Here, we review the current understanding of polyomavirus capsid mutations and their effects on viral tropism, immune evasion, and virulence.
Assuntos
Proteínas do Capsídeo/genética , Evasão da Resposta Imune/genética , Vírus JC/genética , Vírus JC/imunologia , Leucoencefalopatia Multifocal Progressiva/imunologia , Animais , Capsídeo/imunologia , Proteínas do Capsídeo/imunologia , Especificidade de Hospedeiro/genética , Humanos , Evasão da Resposta Imune/imunologia , Leucoencefalopatia Multifocal Progressiva/genética , Leucoencefalopatia Multifocal Progressiva/virologia , Camundongos , Mutação , Tropismo Viral/genética , Replicação Viral/genéticaRESUMO
BACKGROUND: A possible causative role for human papilloma virus (HPV) in cutaneous squamous cell carcinoma (cSCC) development has been suggested but the data in the literature remain discordant. OBJECTIVE: The aim of this study was to investigate the possible association between HPV-16 and the risk of cSCC development. MATERIALS & METHODS: Between January 2009 and April 2010, 153 patients with previous cases of cSCC or BCC (enrolled in a previous study, 2003-2005, and tested for antibodies against 28 HPV types) were investigated at a follow-up visit. The risk of developing a new cSCC for each of the cutaneous HPV types was computed separately for HPV-16-positive and in HPV-16-negative patients. RESULTS: The five-year probability of cSCC recurrence was increased among subjects with cSCC who were seropositive for HPV-16 at baseline and seropositive for a cutaneous HPV type, but not among those who were HPV-16-negative. We also investigated the association between p53, BKV, and JCV antibodies and an increased risk of cSCC recurrence, however, no associations were observed. CONCLUSION: HPV-16 may play a permissive role for some cutaneous HPVs, thus increasing the risk of cSCC.