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Microbiology and Immunology Dec 2020JC polyomavirus (JCPyV) is a common human pathogen that results in a chronic asymptomatic infection in healthy adults. Under conditions of immunosuppression, JCPyV...
JC polyomavirus (JCPyV) is a common human pathogen that results in a chronic asymptomatic infection in healthy adults. Under conditions of immunosuppression, JCPyV spreads to the central nervous system and can cause the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML), a disease for which there are no vaccines or antiviral therapies. Retro-2 is a previously identified small molecule inhibitor that was originally shown to block retrograde transport of toxins such as ricin toxin from endosomes to the Golgi apparatus and endoplasmic reticulum (ER), and Retro-2.1 is a chemical analog of Retro-2 that has been shown to inhibit ricin intoxication of cells at low nanomolar concentrations. Retro-2 has previously been shown to prevent retrograde transport of JCPyV virions to the ER, but the effect of Retro-2.1 on JCPyV infectivity is unknown. Here it is shown that Retro-2.1 inhibits JCPyV with an EC of 3.9 μM. This molecule inhibits JCPyV infection at dosages that are not toxic to human tissue culture cells. Retro-2.1 was also tested against two other polyomaviruses, the human BK polyomavirus and simian virus 40, and was also shown to inhibit infection at similar concentrations. Viral uncoating studies demonstrate that Retro-2.1 inhibits BKPyV infectivity in a manner similar to Retro-2. These studies demonstrate that improved analogs of Retro-2 can inhibit infection at lower dosages than Retro-2 and further optimization of these compounds may lead to effective treatment options for those suffering from JCPyV infection and PML.
Topics: Animals; BK Virus; Benzamides; Chlorocebus aethiops; Humans; JC Virus; Leukoencephalopathy, Progressive Multifocal; Polyomavirus; Polyomavirus Infections; Simian virus 40; Thiophenes; Vero Cells
PubMed: 32965709
DOI: 10.1111/1348-0421.12851 -
Virus Evolution 2021Human polyomaviruses are widespread in humans and can cause severe disease in immunocompromised individuals. To identify human genetic determinants of the humoral immune...
Human polyomaviruses are widespread in humans and can cause severe disease in immunocompromised individuals. To identify human genetic determinants of the humoral immune response against polyomaviruses, we performed genome-wide association studies and meta-analyses of qualitative and quantitative immunoglobulin G responses against BK polyomavirus (BKPyV), JC polyomavirus (JCPyV), Merkel cellpolyomavirus (MCPyV), WU polyomavirus (WUPyV), and human polyomavirus 6 (HPyV6) in 15,660 individuals of European ancestry from three independent studies. We observed significant associations for all tested viruses: JCPyV, HPyV6, and MCPyV associated with human leukocyte antigen class II variation, BKPyV and JCPyV with variants in , responsible for secretor status, MCPyV with variants in , involved in interferon induction, and WUPyV with a functional variant in , previously associated with risk for gastric cancer. These results provide insights into the genetic control of a family of very prevalent human viruses, highlighting genes and pathways that play a modulating role in human humoral immunity.
PubMed: 34532061
DOI: 10.1093/ve/veab058 -
The Journal of Histochemistry and... May 2020BK polyomavirus-associated nephropathy (BKpyVAN) remains a cause of graft loss in kidney transplant recipients on immunosuppressive therapy. Its diagnosis relies on the...
BK polyomavirus-associated nephropathy (BKpyVAN) remains a cause of graft loss in kidney transplant recipients on immunosuppressive therapy. Its diagnosis relies on the identification of BK virus (BKV) in the renal allograft biopsy by positive immunohistochemical (IHC) stain for the viral SV40 large T antigen, although in situ hybridization (ISH) for viral DNA is used in some centers. We examined tissue detection of BKV RNA by RNAscope, a novel, automated ISH test, in 61 allograft biopsies from 56 patients with BKpyVAN. We found good correlation between the estimate of BKV tissue load by RNAscope ISH and SV40 IHC ( = 0.65, 0.0001). RNAscope ISH showed 88% sensitivity and 79% specificity and, as an alternative test, could confirm the presence of BKV tissue in presumed BKpyVAN and rule out BKV as the causative agent in JC virus nephropathy. We also used tissue BK viral load estimates by both RNAscope ISH and SV40 IHC to examine the relation between tissue and plasma BK levels and found significant correlation only between BK viremia and tissue BK measured by RNAscope ISH. Our findings suggest that the RNAscope ISH assay could be a reliable test for BKV detection in allograft biopsies.
Topics: BK Virus; Biopsy; Cohort Studies; DNA, Viral; Female; Humans; Kidney; Kidney Transplantation; Male; Middle Aged; Transplantation, Homologous
PubMed: 32352851
DOI: 10.1369/0022155420922604 -
Journal of Clinical Microbiology Aug 2022Read the full article for the answer.
Read the full article for the answer.
PubMed: 35975991
DOI: 10.1128/jcm.00082-22 -
Acta Medica Indonesiana Apr 2023Progressive multifocal leukoencephalopathy (PML) is a rare, life-threatening, infectious, lytic, demyelinating disease that results from reactivation of the virulent JC...
Progressive multifocal leukoencephalopathy (PML) is a rare, life-threatening, infectious, lytic, demyelinating disease that results from reactivation of the virulent JC polyomavirus (JCV) "major opportunistic infection" in immunosuppressed individuals. We reported a case of a young girl who presented with new onset focal neurological defect, evaluated, and laboratory and radiological findings in the context of a clinical setting confirmed HIV-related-PML infection. However, remyelination does not occur, the patients may develop complications in the long term including cognitive impairment, sensory deficits, motor deficits, and disturbances in balance. We must increase our knowledge about HIV- related PML in any patient with reduced immunity and who presented with new onset neurological defect.
PubMed: 37524599
DOI: No ID Found -
Vaccine Jun 2023Although mumps vaccination has been routine in Canada for decades, mumps cases and outbreaks continue to occur periodically. Mumps surveillance, including monitoring of...
Although mumps vaccination has been routine in Canada for decades, mumps cases and outbreaks continue to occur periodically. Mumps surveillance, including monitoring of the mumps virus genotype associated with disease activity, is important to document baseline activity and to advance further research into vaccine effectiveness. Here we describe a detailed analysis of mumps cases that have been detected in Canada from 2002 to 2020, with a focus on the mumps molecular epidemiology. In total, 7395 cases of mumps were reported to the surveillance system, with outbreaks occurring in the years 2007, 2010 and 2016 to 2018. Adolescents and young adults aged 15 to 29 years had the highest risk of being a case (rate ratios ranging from 1.50 to 2.29), compared to adults aged 30 to 39. Genotypes of mumps viruses were determined in 3225 specimens. Genotype G was predominantly detected (96% of genotyped specimens) and was first reported in 2005. Other genotypes were more likely to be detected in cases that also reported travel (or were linked to imported cases) than the cases with genotype G detected (p < 0.0001). The genotype G viruses had little sequence diversity in the 316 nucleotide window used for genotyping (the small hydrophobic protein gene) and mainly belonged to a single phylogenetic lineage that included the MuVi/Sheffield.GBR/1.05 reference sequence. The analysis of over ten years of data has demonstrated that mumps genotype G, specifically belonging to a single lineage, the Sheffield lineage, is the endemically circulating virus in Canada. This lineage is seen also in other countries using the genotype A vaccine. Mumps remains endemic despite high MMR vaccination coverage which has been sufficient to eliminate circulation of measles and rubella in Canada, raising the hypothesis of the evolution towards a vaccine escape mumps virus.
Topics: Adolescent; Young Adult; Humans; Mumps; Phylogeny; Measles-Mumps-Rubella Vaccine; Mumps virus; Canada; Disease Outbreaks
PubMed: 37169652
DOI: 10.1016/j.vaccine.2023.04.078 -
Nature Communications Mar 2024Influenza virus continuously evolves to escape human adaptive immunity and generates seasonal epidemics. Therefore, influenza vaccine strains need to be updated annually...
Influenza virus continuously evolves to escape human adaptive immunity and generates seasonal epidemics. Therefore, influenza vaccine strains need to be updated annually for the upcoming flu season to ensure vaccine effectiveness. We develop a computational approach, beth-1, to forecast virus evolution and select representative virus for influenza vaccine. The method involves modelling site-wise mutation fitness. Informed by virus genome and population sero-positivity, we calibrate transition time of mutations and project the fitness landscape to future time, based on which beth-1 selects the optimal vaccine strain. In season-to-season prediction in historical data for the influenza A pH1N1 and H3N2 viruses, beth-1 demonstrates superior genetic matching compared to existing approaches. In prospective validations, the model shows superior or non-inferior genetic matching and neutralization against circulating virus in mice immunization experiments compared to the current vaccine. The method offers a promising and ready-to-use tool to facilitate vaccine strain selection for the influenza virus through capturing heterogeneous evolutionary dynamics over genome space-time and linking molecular variants to population immune response.
Topics: Humans; Animals; Mice; Influenza Vaccines; Influenza A Virus, H3N2 Subtype; Hemagglutinin Glycoproteins, Influenza Virus; Influenza, Human; Mutation; Seasons
PubMed: 38514647
DOI: 10.1038/s41467-024-46918-0 -
Nature Communications May 2021By conferring systemic protection and durable benefits, cancer immunotherapies are emerging as long-term solutions for cancer treatment. One such approach that is...
By conferring systemic protection and durable benefits, cancer immunotherapies are emerging as long-term solutions for cancer treatment. One such approach that is currently undergoing clinical testing is a therapeutic anti-cancer vaccine that uses two different viruses expressing the same tumor antigen to prime and boost anti-tumor immunity. By providing the additional advantage of directly killing cancer cells, oncolytic viruses (OVs) constitute ideal platforms for such treatment strategy. However, given that the targeted tumor antigen is encoded into the viral genomes, its production requires robust infection and therefore, the vaccination efficiency partially depends on the unpredictable and highly variable intrinsic sensitivity of each tumor to OV infection. In this study, we demonstrate that anti-cancer vaccination using OVs (Adenovirus (Ad), Maraba virus (MRB), Vesicular stomatitis virus (VSV) and Vaccinia virus (VV)) co-administered with antigenic peptides is as efficient as antigen-engineered OVs and does not depend on viral replication. Our strategy is particularly attractive for personalized anti-cancer vaccines targeting patient-specific mutations. We suggest that the use of OVs as adjuvant platforms for therapeutic anti-cancer vaccination warrants testing for cancer treatment.
Topics: Adjuvants, Immunologic; Animals; Antigens, Neoplasm; Cancer Vaccines; Cell Line, Tumor; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Disease Models, Animal; Female; Humans; Mice; Neoplasms; Oncolytic Virotherapy; Oncolytic Viruses; Poly I-C; Vaccines, Subunit; Vaccinia virus; Vesicular stomatitis Indiana virus; Xenograft Model Antitumor Assays
PubMed: 33976179
DOI: 10.1038/s41467-021-22929-z -
The Lancet. Neurology Aug 2021Progressive multifocal leukoencephalopathy, a rare disease of the CNS caused by JC virus and occurring in immunosuppressed people, is typically fatal unless adaptive...
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 1 × 10 polyomavirus-specific T cells per kg, followed by up to two additional infusions at 2 × 10 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.
Topics: Adult; Aged; BK Virus; Blood Donors; Cohort Studies; Endpoint Determination; Feasibility Studies; Female; Humans; Immunotherapy; JC Virus; Leukoencephalopathy, Progressive Multifocal; Magnetic Resonance Imaging; Male; Middle Aged; Monocytes; Pilot Projects; Survival Analysis; T-Lymphocytes; Treatment Outcome; Young Adult
PubMed: 34302788
DOI: 10.1016/S1474-4422(21)00174-5 -
Asian Pacific Journal of Cancer... Oct 2020JC virus (JCV) , and BK virus (BKV) can remain latency in kidney and excrete via urine asymptomatically. JCV has been associated with colorectal and bladder cancers. BKV...
UNLABELLED
JC virus (JCV) , and BK virus (BKV) can remain latency in kidney and excrete via urine asymptomatically. JCV has been associated with colorectal and bladder cancers. BKV has been linked with lung, pancreas, liver, urogenital tract, head and neck cancers. Therefore, the frequency of JCV DNA and BKV DNA are essential to evaluate in urine samples of healthy individuals.
MATERIALS AND METHODS
Hundred sixty four urine samples were collected from healthy subjects [96 females and 68 males]. DNA was extracted and detection of JCV DNA and BKV DNA was carried out by PCR . The analysis of sequencing and construction of phylogenetic tree were performed for the samples positive for JCV DNA and BKV DNA.
RESULTS
Ten (6.09%) urine samples [5/96(5.2%) females and 5/68( 8.82) males] were tested positive for JCV DNA (P= 0.814). The results of sequencing and phylogenetic tree showed the isolated JCV DNA were cluster with 3A genotype. 21/164 (12.8%) samples were tested positive for BKV DNA [11/96(11.45%) females and males 10/68(14.7%)] ( P= 0.63). The results of sequencing and phylogenetic tree showed that the isolated BKV was cluster with genotype III.
CONCLUSION
In the present study 6.09% and 12.8% of the healthy individuals showed positive for JCV DNA (genotype 3A) and BKV DNA(genotype III) respectively. With regard to life threating diseases by BKV and JCV in immunocomprsied patients , the screening BKV DNA and JCV DNA should be implemented for patients with cancer /autoimmune diseases /organ recipient/ multiple sclerosis (MS), prior to immunosuppression therapy or immunomodulatory agents treatment.
.Topics: Adolescent; Adult; Aged; BK Virus; Child; Child, Preschool; DNA, Viral; Female; Genotype; Healthy Volunteers; Humans; Iran; JC Virus; Male; Middle Aged; Phylogeny; Polyomavirus Infections; Prevalence; Tumor Virus Infections; Young Adult
PubMed: 33112543
DOI: 10.31557/APJCP.2020.21.10.2877