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Neurology(R) Neuroimmunology &... Nov 2019To investigate the effects of natalizumab (NAT) treatment on intrathecally produced antiviral antibodies in MS. (Observational Study)
Observational Study
OBJECTIVE
To investigate the effects of natalizumab (NAT) treatment on intrathecally produced antiviral antibodies in MS.
METHODS
We performed a longitudinal, observational study analyzing both serum and CSF samples collected before and during NAT treatment for antibodies against measles, rubella, mumps, influenza, entero, herpes, and polyoma viruses, including JC polyomavirus (JCV) and its nearest homologue BK polyomavirus (BKV), and bacterial control antigens by ELISA to determine the antigen-specific CSF antibody index (CAI). CAI ≥1.5 indicated intrathecal synthesis of antigen-specific antibodies. Oligoclonal bands (OCBs) by isoelectric focusing and total IgG, IgM, and IgA by immunonephelometry were analyzed additionally.
RESULTS
Intrathecal synthesis of JCV- and BKV-specific IgG was detected in 20% of patients with MS at baseline and was lost significantly more frequently during NAT treatment compared with other intrathecal antiviral and antibacterial antibody reactivities. Peripheral JCV- and BKV-specific antibody responses persisted, and no cross-reactivity between JCV- and BKV-specific CSF antibodies was found. Intrathecal production of antibodies against measles, rubella, and zoster antigens (MRZ reaction) was most prevalent and persisted (73.3% before vs 66.7% after 1 year of NAT therapy). CSF OCBs also persisted (93.3% vs 80.0%), but total CSF IgG and IgM levels declined significantly.
CONCLUSIONS
These data indicate that JCV-specific antibodies are produced intrathecally in a minority of patients with MS, and NAT treatment affects the intrathecal humoral immune response against JCV relatively specifically compared with other neurotropic viruses. Further studies are needed to determine whether this effect translates to higher risk of progressive multifocal leukoencephalopathy development.
Topics: Adolescent; Adult; Antibodies, Viral; Female; Humans; Immunologic Factors; JC Virus; Longitudinal Studies; Male; Middle Aged; Multiple Sclerosis; Natalizumab; Young Adult
PubMed: 31554671
DOI: 10.1212/NXI.0000000000000621 -
Emerging Infectious Diseases Jan 2022Atezolizumab successfully reinvigorated JC virus immunity in a patient in Belgium with progressive multifocal leukoencephalopathy, as demonstrated by clinical,...
Atezolizumab successfully reinvigorated JC virus immunity in a patient in Belgium with progressive multifocal leukoencephalopathy, as demonstrated by clinical, virologic, and radiologic response to treatment. However, the treatment also resulted in immune reconstitution inflammatory syndrome and life-threatening immune-related adverse events. These conditions were treated with corticosteroids, leading to treatment resistance.
Topics: Antibodies, Monoclonal, Humanized; Humans; Immune Reconstitution Inflammatory Syndrome; JC Virus; Leukoencephalopathy, Progressive Multifocal
PubMed: 34856110
DOI: 10.3201/eid2801.204809 -
The Oncogenic Effects, Pathways, and Target Molecules of JC Polyoma Virus T Antigen in Cancer Cells.Frontiers in Oncology 2022JC polyoma virus (JCPyV) is a ubiquitous polyoma virus that infects the individual to cause progressive multifocal leukoencephalopathy and malignancies. Here, we found...
JC polyoma virus (JCPyV) is a ubiquitous polyoma virus that infects the individual to cause progressive multifocal leukoencephalopathy and malignancies. Here, we found that T-antigen knockdown suppressed proliferation, glycolysis, mitochondrial respiration, migration, and invasion, and induced apoptosis and G arrest. The reverse was true for T-antigen overexpression, with overexpression of Akt, survivin, retinoblastoma protein, β-catenin, β-transducin repeat-containing protein (TRCP), and inhibitor of growth (ING)1, and the underexpression of mammalian target of rapamycin (mTOR), phosphorylated (p)-mTOR, p-p38, Cyclin D1, p21, vascular endothelial growth factor (VEGF), ING2, and ING4 in hepatocellular and pancreatic cancer cells and tissues. In lens tumor cells, T antigen transcriptionally targeted viral carcinogenesis, microRNAs in cancer, focal adhesion, p53, VEGF, phosphoinositide 3 kinase-Akt, and Forkhead box O signaling pathways, fructose and mannose metabolism, ribosome biosynthesis, and choline and pyrimidine metabolism. At a metabolomics level, it targeted protein digestion and absorption, aminoacryl-tRNA biosynthesis, biosynthesis of amino acids, and the AMPK signal pathway. At a proteomic level, it targeted ribosome biogenesis in eukaryotes, citrate cycle, carbon metabolism, protein digestion and absorption, aminoacryl-tRNA biosynthesis, extracellular-matrix-receptor interaction, and biosynthesis of amino acids. In lens tumor cells, T antigen might interact with various keratins, ribosomal proteins, apolipoproteins, G proteins, ubiquitin-related proteins, RPL19, β-catenin, β-TRCP, p53, and CCAAT-enhancer-binding proteins in lens tumor cells. T antigen induced a more aggressive phenotype in mouse and human cancer cells due to oncogene activation, inactivation of tumor suppressors, and disruption of metabolism, cell adhesion, and long noncoding RNA-microRNA-target axes.
PubMed: 35350574
DOI: 10.3389/fonc.2022.744886 -
Tropical Medicine and Infectious Disease Dec 2022The polyomaviruses that infect humans, JC virus (JCV) and BK virus (BKV), can establish persistent infections in the cells that make up the renal system, causing...
The polyomaviruses that infect humans, JC virus (JCV) and BK virus (BKV), can establish persistent infections in the cells that make up the renal system, causing nephritis and BKV-associated nephropathy in up to 10% of renal transplant patients, and of these, 90% lose the graft and return for hemodialysis. This study aimed to determine the prevalence of polyomaviruses (PyV) in the population with chronic kidney disease (CKD), classified into three groups (conservative, dialysis, and transplanted) and a control group. Urine samples were collected from 290 individuals, including 202 patients with CKD and 88 from the control group. PyV screening was performed by PCR amplification of a fragment of the VP1 region, and the JCV and BKV species were distinguished through enzymatic digestion with the restriction endonuclease from the amplification of a TAg region. All amplification products were visualized on a 3% agarose gel. The prevalence of PyV infection was correlated with clinical-epidemiological variables using the chi-squared and Fisher's exact tests. In the group with CKD, the prevalence of PyV was 30.2%, a higher rate being observed in conservative patients (36.66%; 22/60), followed by dialysis patients (30.48%; 25/82), and transplanted patients (20%; 12/60). In the control group, the prevalence was 46.59% (41/88). The differentiation between species revealed that JCV was present in 77.8% and BKV in 22.2% of the group with CKD. The prevalence of infection was higher in male patients (59.32%), whose most common pathology was systemic arterial hypertension (35.59%). In the group of transplanted patients, there was a statistically significant association between infection and the use of the immunosuppressant azathioprine ( = 0.015). The prevalence of PyV infection was higher in the control group than in the group with CKD, being predominant in males and in patients with systemic arterial hypertension.
PubMed: 36668916
DOI: 10.3390/tropicalmed8010009 -
Immunobiology 2018Progressive multifocal leukoencephalopathy (PML) is a disease of the central nervous system caused by neuropathogenic prototypes of ubiquitous community-acquired JC... (Review)
Review
Progressive multifocal leukoencephalopathy (PML) is a disease of the central nervous system caused by neuropathogenic prototypes of ubiquitous community-acquired JC virus (JCV). The disease became of particular concern following its association with certain therapies that modulate immune system function without heavy immunosuppression. Due to lack of prophylactic/treatment options and poor outcomes, which often include severe disability or death, PML is a considerable concern for development of new drugs that interfere with immune system functions. In this review of clinical and research findings, we discuss the evidence that deficiencies in CD4 T helper cells, cytotoxic CD8 T cells, and interferon gamma are of crucial importance for development of PML under a variety of circumstances, including those associated with use of various drugs, regardless of differences in their mechanisms of action. These deficiencies apparently enable transformation of the harmless JCV archetype into neuropathogenic prototypes, but the site(s), and the mechanisms, of this transformation are yet to be elucidated. Here we discuss the evidence for brain as one of the sites of this transformation, and propose a model of PML pathogenesis that emphasizes the central role of T cell deficiencies in the two life cycles of the JCV, one non-pathogenic and one neuropathogenic. Finally, we conclude that the development of clinical grade T cell functional tests and more consistent use of already available laboratory tests for T cell subset analysis would greatly aid the effort to more accurately predict and assess the magnitude of PML risk for concerned therapeutic interventions.
Topics: Animals; Brain; Humans; Immunoassay; Immunocompromised Host; Immunotherapy; Interferon-gamma; JC Virus; Leukoencephalopathy, Progressive Multifocal; Risk Factors; T-Lymphocyte Subsets; T-Lymphocytes
PubMed: 29472141
DOI: 10.1016/j.imbio.2018.01.002 -
Journal of Neurology Aug 2021Several viruses have the capacity to cause serious infections of the nervous system in patients who are immunosuppressed. Individuals may be immunosuppressed because of... (Review)
Review
Several viruses have the capacity to cause serious infections of the nervous system in patients who are immunosuppressed. Individuals may be immunosuppressed because of primary inherited immunodeficiency, secondary immunodeficiency due to particular diseases such as malignancy, administration of immunosuppressant drugs or organ or bone marrow transplantation. The viruses capable of such opportunistic infection of the nervous system include herpes simplex virus (HSV), Varicella-Zoster virus (VZV), Cytomegalovirus (CMV), Epstein -Barr virus (EBV), Human Herpes virus type 6 (HHV-6), JC virus (JCV), enterovirus, measles virus and Covid-19. In most cases it seems likely that immunological defence mechanisms in the immunosuppressed are deficient which creates a suitable environment for certain viruses to become opportunistic in the nervous and other systems. Further research is required both to understand these opportunistic mechanisms in more detail and also to determine how many virus infections are modified by specific inborn errors of immunological responses.
Topics: COVID-19; Herpesviridae Infections; Herpesvirus 3, Human; Humans; Immunocompromised Host; Nervous System; Nervous System Diseases; SARS-CoV-2; Virus Diseases
PubMed: 33048220
DOI: 10.1007/s00415-020-10265-z -
The New England Journal of Medicine Apr 2019
Topics: Antibodies, Monoclonal, Humanized; Humans; JC Virus; Leukoencephalopathy, Progressive Multifocal; Natalizumab
PubMed: 30969502
DOI: 10.1056/NEJMe1904140 -
Microbiology Spectrum Jan 2017As the "human microbiome era" continues, there is an increasing awareness of our resident microbiota and its indispensable role in our fitness as holobionts. However,... (Review)
Review
As the "human microbiome era" continues, there is an increasing awareness of our resident microbiota and its indispensable role in our fitness as holobionts. However, the host-microbe relationship is not so clearly defined for some human symbionts. Here we discuss examples of "accidental pathogens," meaning previously nonpathogenic and/or environmental microbes thought to have inadvertently experienced an evolutionary shift toward pathogenicity. For instance, symbionts such as Helicobacter pylori and JC polyomavirus have been shown to have accompanied humans since prehistoric times and are still abundant in extant populations as part of the microbiome. And yet, the relationship between a subgroup of these microbes and their human hosts seems to have changed with time, and they have recently gained notoriety as gastrointestinal and neuropathogens, respectively. On the other hand, environmental microbes such as Legionella spp. have recently experienced a shift in host range and are now a major problem in industrialized countries as a result of artificial ecosystems. Other variables involved in this accidental phenomenon could be the apparent change or reduction in the diversity of human-associated microbiota because of modern medicine and lifestyles. All of this could result in an increased prevalence of accidental pathogens in the form of emerging pathogens.
Topics: Animals; Biological Evolution; Helicobacter pylori; Host-Pathogen Interactions; Humans; JC Virus; Legionella
PubMed: 28155809
DOI: 10.1128/microbiolspec.EMF-0009-2016 -
Frontiers in Immunology 2015Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease due to JC virus (JCV) replication in the brain. PML classically occurs in patients... (Review)
Review
Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease due to JC virus (JCV) replication in the brain. PML classically occurs in patients with severe immunodepression, and cases have recently been linked to therapeutic monoclonal antibodies such as natalizumab and also rituximab, which depletes B cells. B cells appear to play a complex role in the pathogenesis of PML. They may act as a viral reservoir and as a vector for viral dissemination in the central nervous system. Anti-JCV antibody responses appear to have a limited effect on JCV replication in the brain. However, accumulating evidence suggests that B cells may considerably influence T cell responses through their cytokine secretion. This immunomodulatory function of B cells may play an important role in the control of JCV infection and in the pathogenesis of PML, including rituximab-induced PML.
PubMed: 26042124
DOI: 10.3389/fimmu.2015.00241 -
Uirusu 2015Viroporins are small and hydrophobic viral proteins that form pores on host cell membranes, and their expression can increase the permeability of cellular membranes and... (Review)
Review
Viroporins are small and hydrophobic viral proteins that form pores on host cell membranes, and their expression can increase the permeability of cellular membranes and the production of progeny virus particles. JC virus (JCV) is the causative agent of progressive multifocal leukoenchephalopathy (PML). We demonstrate that JCV Agno, which is the small and hydrophobic protein, andincreases the plasma membrane permeability and virion release, acts as a viroporin. We also demonstrate that an interaction of Agno with a host cellular protein regulates the viroporin activity of Agno. These findings indicate a new paradigm in virus-host interactions regulating viroporin activity and viral replication.
Topics: Cell Membrane Permeability; Host-Pathogen Interactions; Humans; JC Virus; Leukoencephalopathy, Progressive Multifocal; Membrane Lipids; Viral Regulatory and Accessory Proteins; Virion; Virus Replication
PubMed: 26923968
DOI: 10.2222/jsv.65.135