-
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 -
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 -
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 -
Advances in Therapy Jul 2021STRIVE was a 4-year, multicenter, observational, open-label, single-arm study of natalizumab treatment in anti-JC virus antibody-negative (JCV-negative)... (Observational Study)
Observational Study
INTRODUCTION
STRIVE was a 4-year, multicenter, observational, open-label, single-arm study of natalizumab treatment in anti-JC virus antibody-negative (JCV-negative) relapsing-remitting multiple sclerosis (RRMS) patients with disease duration ≤ 3 years. The objective of STRIVE was to examine no evidence of disease activity (NEDA) status and predictors of NEDA in natalizumab-treated patients with early RRMS.
METHODS
Proportions of patients with NEDA were evaluated along with baseline predictors of NEDA, annualized relapse rate, 24-week confirmed disability worsening (CDW), magnetic resonance imaging assessments (T2 and gadolinium-enhancing lesions), and serious adverse events.
RESULTS
In years 1 and 2, 56.1% (95% confidence interval [CI] 48.7-63.4%) and 73.6% (95% CI 66.2-80.2%) of patients (intent-to-treat population [N = 222]), respectively, achieved NEDA. In years 3 and 4, 84.6% (95% CI 78.0-89.9%) and 91.9% (95% CI 86.4-95.8%) of patients, respectively, achieved Clinical NEDA (no relapses or 24-week CDW). Baseline predictors of NEDA in year 4 were Expanded Disability Status Scale score ≤ 2.0 (odds ratio [OR] = 3.85 [95% CI 1.54-9.63]; p = 0.004) and T2 lesion volume > 4 cc (OR = 0.39 [95% CI 0.15-0.98]; p = 0.046), with the latter also predicting Clinical NEDA in year 4 (OR = 0.21 [95% CI 0.05-0.92]; p = 0.038). The cumulative probability of CDW at year 4 was 19.3%. Serious adverse events were reported in 11.3% of patients.
CONCLUSION
These results support the long-term safety and effectiveness of natalizumab. Baseline predictors of NEDA help to inform benefit-risk assessments of natalizumab treatment in JCV-negative patients with early RRMS.
TRIAL REGISTRATION
ClinicalTrials.gov identifier NCT01485003.
Topics: Humans; Immunologic Factors; Magnetic Resonance Imaging; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Treatment Outcome
PubMed: 34014549
DOI: 10.1007/s12325-021-01722-w -
Brain and Nerve = Shinkei Kenkyu No... Oct 2022Here, an overview of progressive multifocal leukoencephalopathy (PML) and its drug associations, especially the disease-modifying drug (DMD)-associated PML for multiple... (Review)
Review
Here, an overview of progressive multifocal leukoencephalopathy (PML) and its drug associations, especially the disease-modifying drug (DMD)-associated PML for multiple sclerosis (MS) were discussed. Additionally, along with presenting the current status of PML in MS caused by natalizumab, fingolimod, and dimethyl fumarate, the possibility of PML onset with siponimod and ofatumumab, the two newly proposed DMDs for MS, was provided. PML treatment in the era of DMD-associated PML, especially PML in MS, is an important issue. With respect to the treatment of PML, to date, there are no specific antiviral drugs against the JC virus; some drugs, that may have therapeutic potential reported recently, were also mentioned.
Topics: Antiviral Agents; Dimethyl Fumarate; Fingolimod Hydrochloride; Humans; JC Virus; Leukoencephalopathy, Progressive Multifocal; Multiple Sclerosis; Natalizumab
PubMed: 36198643
DOI: 10.11477/mf.1416202206 -
The Journal of Infectious Diseases Oct 2021Human polyomaviruses can reactivate in transplant patients, causing nephropathy, progressive multifocal leukoencephalopathy, Merkel cell carcinoma, pruritic, rash or...
BACKGROUND
Human polyomaviruses can reactivate in transplant patients, causing nephropathy, progressive multifocal leukoencephalopathy, Merkel cell carcinoma, pruritic, rash or trichodysplasia spinulosa. Sirolimus and related mechanistic target of rapamycin (mTOR) inhibitors are transplant immunosuppressants. It is unknown if they directly reactivate polyomavirus replication from latency beyond their general effects on immunosuppression.
METHODS
In vitro expression and turnover of large T (LT) proteins from BK virus, JC virus (JCV), Merkel cell polyomavirus (MCV), human polyomavirus 7 (HPyV7), and trichodysplasia spinulosa polyomavirus (TSV) after drug treatment were determined by immunoblotting, proximity ligation, replicon DNA replication, and whole virus immunofluorescence assays.
RESULTS
mTOR inhibition increased LT protein expression for all 5 pathogenic polyomaviruses tested. This correlated with LT stabilization, decrease in the S-phase kinase-associated protein 2 (Skp2) E3 ligase targeting these LT proteins for degradation, and increase in virus replication for JCV, MCV, TSV, and HPyV7. Treatment with sirolimus, but not the calcineurin inhibitor tacrolimus, at levels routinely achieved in patients, resulted in a dose-dependent increase in viral DNA replication for BKV, MCV, and HPyV7.
CONCLUSIONS
mTOR inhibitors, at therapeutic levels, directly activate polyomavirus replication through a Skp2-dependent mechanism, revealing a proteostatic latency mechanism common to polyomaviruses. Modifying existing drug regimens for transplant patients with polyomavirus-associated diseases may reduce symptomatic polyomavirus replication while maintaining allograft-sparing immunosuppression.
Topics: BK Virus; DNA Replication; DNA, Viral; Humans; JC Virus; MTOR Inhibitors; Merkel cell polyomavirus; Polyomavirus; Polyomavirus Infections; S-Phase Kinase-Associated Proteins; Sirolimus; TOR Serine-Threonine Kinases; Tacrolimus; Virus Replication
PubMed: 32060513
DOI: 10.1093/infdis/jiaa071 -
Journal of Virology Mar 2021JC polyomavirus (JCPyV) infects the majority of the population, establishing a lifelong, asymptomatic infection in the kidney of healthy individuals. People that become...
JC polyomavirus (JCPyV) infects the majority of the population, establishing a lifelong, asymptomatic infection in the kidney of healthy individuals. People that become severely immunocompromised may experience JCPyV reactivation, which can cause progressive multifocal leukoencephalopathy (PML), a neurodegenerative disease. Due to a lack of therapeutic options, PML results in fatality or significant debilitation among affected individuals. Cellular internalization of JCPyV is mediated by serotonin 5-hydroxytryptamine subfamily 2 receptors (5-HTRs) via clathrin-mediated endocytosis. The JCPyV entry process requires the clathrin-scaffolding proteins β-arrestin, adaptor protein 2 (AP2), and dynamin. Further, a β-arrestin interacting domain, the Ala-Ser-Lys (ASK) motif, within the C-terminus of 5-HTR is important for JCPyV internalization and infection. Interestingly, 5-HTR subtypes A, B, and C equally support JCPyV entry and infection, and all subtypes contain an ASK motif, suggesting a conserved mechanism for viral entry. However, the role of the 5-HTR ASK motifs and the activation of β-arrestin-associated proteins during internalization has not been fully elucidated. Through mutagenesis, the ASK motifs within 5-HTR and 5-HTR were identified as critical for JCPyV internalization and infectivity. Further, utilizing biochemical pulldown techniques, mutagenesis of the ASK motifs in 5-HTR and 5-HTR resulted in reduced β-arrestin binding. Utilizing small-molecule chemical inhibitors and RNA interference, G-protein receptor kinase 2 (GRK2) was determined to be required for JCPyV internalization and infection by mediating interactions between β-arrestin and the ASK motif of 5-HTRs. These findings demonstrate that GRK2 and β-arrestin interactions with 5-HTRs are critical for JCPyV entry by clathrin-mediated endocytosis and resultant infection. As intracellular parasites, viruses require a host cell to replicate and cause disease. Therefore, virus-host interactions contribute to viral pathogenesis. JC polyomavirus (JCPyV) infects most of the population, establishing a lifelong asymptomatic infection within the kidney. Under conditions of severe immunosuppression JCPyV may spread to the central nervous system, causing the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). Individuals living with HIV or undergoing immunomodulatory therapies are at risk for developing PML. The mechanisms of how JCPyV uses specific receptors on the surface of host cells to initiate internalization and infection is a poorly understood process. We have further identified cellular proteins involved in JCPyV internalization and infection and elucidated their specific interactions that are responsible for activation of receptors. Collectively, these findings illuminate how viruses usurp cellular receptors during infection, contributing to current development efforts for therapeutic options for the treatment or prevention of PML.
PubMed: 33441347
DOI: 10.1128/JVI.02139-20 -
BioRxiv : the Preprint Server For... Dec 2022Prime-boost regimens for COVID-19 vaccines elicit poor antibody responses against Omicron-based variants and employ frequent boosters to maintain antibody levels. We...
Prime-boost regimens for COVID-19 vaccines elicit poor antibody responses against Omicron-based variants and employ frequent boosters to maintain antibody levels. We present a natural infection-mimicking technology that combines features of mRNA- and protein nanoparticle-based vaccines through encoding self-assembling enveloped virus-like particles (eVLPs). eVLP assembly is achieved by inserting an ESCRT- and ALIX-binding region (EABR) into the SARS-CoV-2 spike cytoplasmic tail, which recruits ESCRT proteins to induce eVLP budding from cells. Purified spike-EABR eVLPs presented densely-arrayed spikes and elicited potent antibody responses in mice. Two immunizations with mRNA-LNP encoding spike-EABR elicited potent CD8+ T-cell responses and superior neutralizing antibody responses against original and variant SARS-CoV-2 compared to conventional spike-encoding mRNA-LNP and purified spike-EABR eVLPs, improving neutralizing titers >10-fold against Omicron-based variants for three months post-boost. Thus, EABR technology enhances potency and breadth of vaccine-induced responses through antigen presentation on cell surfaces and eVLPs, enabling longer-lasting protection against SARS-CoV-2 and other viruses.
PubMed: 36597535
DOI: 10.1101/2022.12.26.521940 -
Expert Opinion on Drug Safety 2023Progressive multifocal leukoencephalopathy (PML), an important identified risk for natalizumab, has been described for standard interval dosing (SID; dosing interval...
BACKGROUND
Progressive multifocal leukoencephalopathy (PML), an important identified risk for natalizumab, has been described for standard interval dosing (SID; dosing interval every-4-weeks). Information on PML with natalizumab extended interval dosing (EID; dosing interval >every-4-weeks) in the US and the rest of the world (ROW) is limited.
RESEARCH DESIGN AND METHODS
A retrospective analysis of patient demographics, risk factors, clinical characteristics, and clinical outcomes was conducted on confirmed natalizumab EID and SID PML cases evaluated from Biogen pharmacovigilance systems.
RESULTS
Of 857 confirmed natalizumab PML cases, EID and SID accounted for 7.5% and 92.5%, respectively (US: 12.9% and 87.1%; ROW: 5.4% and 94.6%). PML risk factors included anti-JCV index > 1.5 (US: EID, 56.7% and SID, 12.8%; ROW: EID, 44.1% and SID, 21.0%), mean duration of natalizumab treatment (US: 90.0 and 70.2 months; ROW: 54.1 and 49.8 months), and prior immunosuppressive therapy (US: 20.0% and 21.7%; ROW:11.8% and 18.0%). In the EID and SID groups, 68.8% and 76.0% of patients, respectively, were alive at up to 2 years after diagnosis.
CONCLUSIONS
This analysis provides insights on PML in patients receiving natalizumab that extend current knowledge, particularly regarding PML in patients receiving natalizumab EID, which can be built upon in the future.
Topics: Humans; United States; Natalizumab; Leukoencephalopathy, Progressive Multifocal; Retrospective Studies; Immunosuppressive Agents; Risk Factors; Multiple Sclerosis; Immunologic Factors; JC Virus
PubMed: 37272350
DOI: 10.1080/14740338.2023.2221027