-
Neurology(R) Neuroimmunology &... Nov 2023Natalizumab, a monoclonal humanized antibody targeting integrin α4, inhibits the transmigration of lymphocytes into the CNS by preventing the interaction of integrin...
BACKGROUND AND OBJECTIVES
Natalizumab, a monoclonal humanized antibody targeting integrin α4, inhibits the transmigration of lymphocytes into the CNS by preventing the interaction of integrin α4β1 with V-CAM expressed on brain vascular endothelial cells. Although natalizumab treatment reduces the clinical relapse rate in patients with relapsing-remitting MS, its discontinuation after reactivation of the JC virus is associated with a rebound of the disease in 20% of patients. The mechanisms of this rebound are not elucidated, but natalizumab increases the frequencies of circulating CD4 T cells expressing proinflammatory cytokines as well as the proportion of circulating Th17/Th1 cells (Th1-like Th17 cells). Gut-derived memory CD4 T cells are a population of growing interest in the pathogenesis of MS, but whether and how their properties are affected by natalizumab is not known. Here, we studied the phenotype and cytokine expression profile of circulating gut-derived memory CD4 T cells in patients with relapsing-remitting MS under natalizumab.
METHODS
We identified gut-derived memory CD4 T cells by their expression of integrin β7 and compared their properties and those of integrin β7- memory CD4 T cells across healthy donors and patients with relapsing-remitting MS treated or not with natalizumab. We also compared the capacity of integrin β7- and integrin β7+ CD4 T-cell subsets to transmigrate in vitro across a model of blood-brain barrier.
RESULTS
The proportions of proinflammatory Th17/Th1 cells as well as of IL-17A+IFNγ+ and IL-17A+GM-CSF+ cells were higher in memory CD4 T cells expressing integrin β7 in patients receiving natalizumab compared with healthy donors and patients with relapsing-remitting MS not receiving natalizumab. By contrast, integrin β7 negative memory CD4 T cells only presented a modest increased in their proportion of Th17/Th1 cells under natalizumab. We further observed that integrin β7+ Th17/Th1 cells migrated as efficiently as integrin β7- Th17/Th1 across a monolayer of brain microvascular endothelial cells.
DISCUSSION
Our study shows that circulating integrin β7+ memory CD4 T cells of patients with relapsing-remitting MS under natalizumab are enriched in proinflammatory cells supporting the hypothesis that integrin β7+ memory CD4 T cells could play a pathogenic role in the disease rebound observed at natalizumab discontinuation.
Topics: Humans; CD4-Positive T-Lymphocytes; Natalizumab; Interleukin-17; Endothelial Cells; Antibodies, Monoclonal
PubMed: 37739811
DOI: 10.1212/NXI.0000000000200166 -
Brain, Behavior, & Immunity - Health Aug 2021Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the white matter central nervous system occurring in immunocompromised patients...
Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the white matter central nervous system occurring in immunocompromised patients particularly those with T cell deficiency such as in HIV, haematological and solid organ malignancies and those taking immunomodulatory medications. PML is caused by JC virus however in rare cases BK virus has been isolated in the cerebral spinal fluid of patients presenting with PML. In this case we describe a 49 year old man who presented to the emergency department with a 2 week history of progressive right sided weakness and dysarthria. His background history included HIV diagnosed in 2005, he had not engaged with care in the past 2 years and had not been taking anti-retroviral therapy (ART). Other past medical history included untreated hepatitis C. His CD4 count was 90 (11%) cells/mm on admission and his HIV viral load VL) was 141,000 copies/ml. Magnetic resonance imaging(MRI) showed a hypointense lesion on T1, hyperintense on T2 and FLAIR without diffusion restriction and without mass effect. A lumbar puncture was performed which confirmed JC virus was positive (PCR <50 copies/ml) and also revealed BK virus was positive (PCR 46,511 copies/ml). The patient was commenced on tenofovir alafenamide fumarate/emtricitabine/darunavir/cobicistat in combination with dolutegravir 50mg twice daily. On day 40 post commencement of ART the patient was readmitted with worsening of his right arm weakness and dysarthria. A repeat MRI was performed which showed the hyperdense lesion on T2 and FLAIR appeared slightly larger with some slight enhancement with gadolinium contrast but no other features suggesting PML immune reconstitution inflammatory syndrome (IRIS). The CD4 count had increased to 141(17%) and HIV VL had decreased to 85 copies/ml. A clinical diagnosis of PML IRIS was made and the patient was commenced on prednisolone 30mg BD which lead to an initial improvement in symptoms. Interestingly in this case, both JC virus and BK virus were detected in the CSF of this patient with the level of JC virus being too low to quantify. BK virus was not detectable on peripheral serum sampling suggesting that BK virus is replicating in the CNS independent of other body sites. There have been 5 case reports in the literature of BK virus as the cause of PML. Testing for BK virus should be considered in patients presenting with signs and symptoms of PML and encephalitis particularly when no other cause is found.
PubMed: 34589769
DOI: 10.1016/j.bbih.2021.100263 -
Journal of Neurovirology Feb 2022Progressive multifocal leukoencephalopathy (PML) is a frequent neurological complication in immunosuppressed patients. PML is caused by the JC virus (JCV), a neurotropic...
Progressive multifocal leukoencephalopathy (PML) is a frequent neurological complication in immunosuppressed patients. PML is caused by the JC virus (JCV), a neurotropic DNA polyomavirus that infects oligodendrocytes and astrocytes, causing inflammation and demyelination which lead to neurological dysfunction. The pathogenesis of PML is poorly understood due to the lack of in vitro or animal models to study mechanisms of disease as the virus most efficiently infects only human cells. We developed a human-derived brain organotypic system (also called brain organoid) to model JCV infection. The model was developed by using human-induced pluripotent stem cells (iPSC) and culturing them in 3D to generate an organotypic model containing neurons, astrocytes, and oligodendrocytes which recapitulates aspects of the environment of the human brain. We infected the brain organoids with the JCV MAD4 strain or cerebrospinal fluid of a patient with PML. The organoids were assessed for evidence of infection by qPCR, immunofluorescence, and electron microscopy at 1, 2, and 3 weeks post-exposure. JCV infection in both JCV MAD4 strain and PML CSF-exposed brain organoids was confirmed by immunocytochemical studies demonstrating viral antigens and electron microscopy showing virion particles in the nuclear compartment of oligodendrocytes and astrocytes. No evidence of neuronal infection was visualized. Infection was also demonstrated by JCV qPCR in the virus-exposed organoids and their media. In conclusion, the brain organoid model of JCV infection establishes a human model suitable for studying the mechanisms of JCV infection and pathogenesis of PML and may facilitate the exploration of therapeutic approaches.
Topics: Animals; Brain; DNA, Viral; Humans; JC Virus; Leukoencephalopathy, Progressive Multifocal; Organoids; Polyomavirus Infections
PubMed: 35239145
DOI: 10.1007/s13365-022-01062-7 -
Molecules (Basel, Switzerland) Aug 2020The arbocyclic nucleosides aristeromycin and neplanocin have been studied as a source for new antiviral agents. A convenient synthesis of C-5'-truncated...
The arbocyclic nucleosides aristeromycin and neplanocin have been studied as a source for new antiviral agents. A convenient synthesis of C-5'-truncated 3-deaza-1',6'-isoneplanocin, which combines the features of antiviral candidates 5'-noraristeromycin and 3-deaza-1',6'-isoneplanocin is reported from (-)-cyclopentenone to give the two C-4' epimers of 5'-nor-3-deaza isoneplanocin. Antiviral assays showed activity against the JC virus (EC = 1.12 µM for (4')-; EC = 59.14 µM for (4')-) and inactivity of both compounds against several DNA and RNA viruses. Both compounds lacked cytotoxicity.
Topics: Adenosine; Antiviral Agents; Humans; JC Virus; RNA Viruses
PubMed: 32854369
DOI: 10.3390/molecules25173865 -
Proceedings of the National Academy of... Aug 2023There has long been controversy over the potential for asymptomatic cases of the influenza virus to have the capacity for onward transmission, but recognition of...
There has long been controversy over the potential for asymptomatic cases of the influenza virus to have the capacity for onward transmission, but recognition of asymptomatic transmission of COVID-19 stimulates further research into this topic. Here, we develop a Bayesian methodology to analyze detailed data from a large cohort of 727 households and 2515 individuals in the 2009 pandemic influenza A(H1N1) outbreak in Hong Kong to characterize household transmission dynamics and to estimate the relative infectiousness of asymptomatic versus symptomatic influenza cases. The posterior probability that asymptomatic cases [36% of cases; 95% credible interval (CrI): 32%, 40%] are less infectious than symptomatic cases is 0.82, with estimated relative infectiousness 0.57 (95% CrI: 0.11, 1.54). More data are required to strengthen our understanding of the contribution of asymptomatic cases to the spread of influenza.
Topics: Humans; Influenza, Human; Influenza A Virus, H1N1 Subtype; Bayes Theorem; COVID-19; Disease Outbreaks
PubMed: 37549267
DOI: 10.1073/pnas.2304750120 -
Behavior Genetics Jan 2022The corona virus disease 2019 (COVID-19) pandemic and the restrictions to reduce the spread of the virus has had a large impact on daily life. We investigated the...
The corona virus disease 2019 (COVID-19) pandemic and the restrictions to reduce the spread of the virus has had a large impact on daily life. We investigated the individual differences in the effect of the COVID-19 pandemic and first lockdown on optimism and meaning in life in a sample from the Netherlands Twin Register. Participants completed surveys before (N = 9964, Mean age: 48.2, SD = 14.4) and during the first months of the pandemic (i.e. April-May 2020, N = 17,464, Mean age: 44.6 SD = 14.8), with a subsample completing both surveys (N = 6461, Mean age T1: 48.8, SD = 14.5). We applied genetic covariance structure models to twin data to investigate changes in the genetic architecture of the outcome traits due to the pandemic and the interaction of genes with the environmental exposure. Although 56% and 35% of the sample was negatively affected by the pandemic in their optimism and meaning in life, many participants were stable (32% and 43%) or even showed increased optimism and meaning in life (11% and 22%). Subgroups, specifically women, higher educated people, and people with poorer health, experienced larger negative effects. During the first months of the pandemic, slightly lower heritability estimates for optimism and meaning in life (respectively 20% and 25%) were obtained compared to pre-pandemic (respectively 26% and 32%), although confidence intervals overlap. The lower than unity genetic correlations across time (.75 and .63) suggest gene-environment interactions, where the expression of genes that influence optimism and meaning in life differs before and during the pandemic. The COVID-19 pandemic is a strong exposure that leads to imbalanced effects on the well-being of individuals. Some people decrease in well-being, while others get more optimistic and consider their lives as more meaningful during the pandemic. These differences are partly explained by individual differences in genetic sensitivity to extreme environmental change. More knowledge on the person-specific response to specific environmental variables underlying these individual differences is urgently needed to prevent further inequality.
Topics: Adult; COVID-19; Communicable Disease Control; Female; Gene-Environment Interaction; Humans; Male; Middle Aged; Netherlands; Optimism; Pandemics; Registries; Twins
PubMed: 34518922
DOI: 10.1007/s10519-021-10081-9 -
Journal of Neurology May 2023Natalizumab (NTZ) and ocrelizumab (OCR) can be used for the treatment of relapsing-remitting multiple sclerosis (RRMS). In patients treated with NTZ, screening for JC... (Observational Study)
Observational Study Randomized Controlled Trial
BACKGROUND
Natalizumab (NTZ) and ocrelizumab (OCR) can be used for the treatment of relapsing-remitting multiple sclerosis (RRMS). In patients treated with NTZ, screening for JC virus (JCV) is mandatory, and a positive serology usually requires a change in treatment after 2 years. In this study, JCV serology was used as a natural experiment to pseudo-randomize patients into NTZ continuation or OCR.
METHODS
An observational analysis of patients who had received NTZ for at least 2 years and were either changed to OCR or maintained on NTZ, depending on JCV serology status, was performed. A stratification moment (STRm) was established when patients were pseudo-randomized to either arm (NTZ continuation if JCV negativity, or change to OCR if JCV positivity). Primary endpoints include time to first relapse and presence of relapses after STRm and OCR initiation. Secondary endpoints include clinical and radiological outcomes after 1 year.
RESULTS
Of the 67 patients included, 40 continued on NTZ (60%) and 27 were changed to OCR (40%). Baseline characteristics were similar. Time to first relapse was not significantly different. Ten patients in the JCV + OCR arm presented a relapse after STRm (37%), four during the washout period, and 13 patients in the JCV-NTZ arm (32.5%, p = 0.701). No differences in secondary endpoints were detected in the first year after STRm.
CONCLUSIONS
The JCV status can be used as a natural experiment to compare treatment arms with a low selection bias. In our study, switching to OCR versus NTZ continuation led to similar disease activity outcomes.
Topics: Humans; Natalizumab; Multiple Sclerosis, Relapsing-Remitting; JC Virus; Risk Assessment; Immunologic Factors; Leukoencephalopathy, Progressive Multifocal
PubMed: 36913038
DOI: 10.1007/s00415-023-11645-x -
Intercellular Transmission of Naked Viruses through Extracellular Vesicles: Focus on Polyomaviruses.Viruses Sep 2020Extracellular vesicles have recently emerged as a novel mode of viral transmission exploited by naked viruses to exit host cells through a nonlytic pathway.... (Review)
Review
Extracellular vesicles have recently emerged as a novel mode of viral transmission exploited by naked viruses to exit host cells through a nonlytic pathway. Extracellular vesicles can allow multiple viral particles to collectively traffic in and out of cells, thus enhancing the viral fitness and diversifying the transmission routes while evading the immune system. This has been shown for several RNA viruses that belong to the Picornaviridae, Hepeviridae, Reoviridae, and Caliciviridae families; however, recent studies also demonstrated that the BK and JC viruses, two DNA viruses that belong to the Polyomaviridae family, use a similar strategy. In this review, we provide an update on recent advances in understanding the mechanisms used by naked viruses to hijack extracellular vesicles, and we discuss the implications for the biology of polyomaviruses.
Topics: Antibodies, Neutralizing; Antibodies, Viral; Endocytosis; Extracellular Vesicles; Humans; Immune Evasion; Polyomavirus; Polyomavirus Infections; Tumor Virus Infections; Virus Internalization; Virus Replication
PubMed: 32993049
DOI: 10.3390/v12101086 -
Journal of Clinical Virology : the... Oct 2021Human polyomaviruses (HPyVs) cause disease in immunocompromised patients. BK polyomavirus (BKPyV) for instance persistently infects the kidneys. In kidney transplant...
INTRODUCTION
Human polyomaviruses (HPyVs) cause disease in immunocompromised patients. BK polyomavirus (BKPyV) for instance persistently infects the kidneys. In kidney transplant recipients, (KTRs) BKPyV can cause allograft nephropathy. JCPyV, MCPyV, TSPyV and HPyV9 reside in the kidneys too, or have been detected in urine. In this study, we investigate exposure to JCPyV, MCPyV, TSPyV and HPyV9 after kidney transplantation by serological means.
MATERIALS AND METHODS
Serum samples from 310 KTR collected before and 6 months after transplantation (n = 620), from 279 corresponding kidney donors collected before transplantation, and from blood donor controls collected one year apart (n = 174) were assessed for HPyV species-specific IgG responses using a multiplex immunoassay. KTR HPyV IgG kinetics were compared to those of healthy blood donors by linear mixed modeling, and related to those of their donors by linear regression.
RESULTS
In the KTR, increased IgG levels during follow-up were observed for JCPyV (14.8%), MCPyV (7.1%), TSPyV (10.6%), and for HPyV9 (8.1%), while blood donor antibody levels remained stable. Seroconversion was observed for JCPyV (6.5%), MCPyV (2.3%), TSPyV (1.3%), and for HPyV9 (6.5%). The linear mixed model analysis showed that antibody increase was significant for JCPyV (p < 0.001) and HPyV9 (p < 0.001). Post-transplant JCPyV and HPyV9 antibody responses were associated with donor antibody levels against these HPyVs, respectively.
CONCLUSIONS
KTR are exposed to JCPyV and HPyV9 after transplantation. Whether the allograft serves as the source, as indicated by the donor serostatus association, deserves further study.
Topics: BK Virus; Blood Donors; Cohort Studies; Humans; JC Virus; Kidney Transplantation; Polyomaviridae; Polyomavirus; Polyomavirus Infections; Tumor Virus Infections
PubMed: 34450559
DOI: 10.1016/j.jcv.2021.104944 -
Journal of Neuroimmune Pharmacology :... Dec 2019With the advent of immunomodulatory therapies and the HIV epidemic, the impact of JC Virus (JCV) on the public health system has grown significantly due to the increased... (Review)
Review
With the advent of immunomodulatory therapies and the HIV epidemic, the impact of JC Virus (JCV) on the public health system has grown significantly due to the increased incidence of Progressive Multifocal Leukoencephalopathy (PML). Currently, there are no pharmaceutical agents targeting JCV infection for the treatment and the prevention of viral reactivation leading to the development of PML. As JCV primarily reactivates in immunocompromised patients, it is proposed that the immune system (mainly the cellular-immunity component) plays a key role in the regulation of JCV to prevent productive infection and PML development. However, the exact mechanism of JCV immune regulation and reactivation is not well understood. Likewise, the impact of host factors on JCV regulation and reactivation is another understudied area. Here we discuss the current literature on host factor-mediated and immune factor-mediated regulation of JCV gene expression with the purpose of developing a model of the factors that are bypassed during JCV reactivation, and thus are potential targets for the development of therapeutic interventions to suppress PML initiation. Graphical Abstract.
Topics: Animals; Host Microbial Interactions; Humans; Immunocompromised Host; Immunotherapy; JC Virus; Leukoencephalopathy, Progressive Multifocal; Virus Activation
PubMed: 31452013
DOI: 10.1007/s11481-019-09877-8