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Vaccines May 2024We assessed the impact of respiratory syncytial virus (RSV) preventive characteristics on the intentions of pregnant people and healthcare providers (HCPs) to protect...
We assessed the impact of respiratory syncytial virus (RSV) preventive characteristics on the intentions of pregnant people and healthcare providers (HCPs) to protect infants with a maternal vaccine or monoclonal antibodies (mAbs). Pregnant people and HCPs who treated pregnant people and/or infants were recruited via convenience sample from a general research panel to complete a cross-sectional, web-based survey, including a discrete choice experiment (DCE) wherein respondents chose between hypothetical RSV preventive profiles varying on five attributes (effectiveness, preventive type [maternal vaccine vs. mAb], injection recipient/timing, type of medical visit required to receive the injection, and duration of protection during RSV season) and a no-preventive option. A best-worst scaling (BWS) exercise was included to explore the impact of additional attributes on preventive preferences. Data were collected between October and November 2022. Attribute-level preference weights and relative importance (RI) were estimated. Overall, 992 pregnant people and 310 HCPs participated. A preventive (vs. none) was chosen 89.2% (pregnant people) and 96.0% (HCPs) of the time (DCE). Effectiveness was most important to preventive choice for pregnant people (RI = 48.0%) and HCPs (RI = 41.7%); all else equal, pregnant people (RI = 5.5%) and HCPs (RI = 7.2%) preferred the maternal vaccine over mAbs, although preventive type had limited influence on choice. Longer protection, protection starting at birth or the beginning of RSV season, and use for both pre-term and full-term babies were ranked highest in importance (BWS). Pregnant people and HCPs strongly preferred a preventive to protect infants against RSV (vs. none), underscoring the need to incorporate RSV preventives into routine care.
PubMed: 38793811
DOI: 10.3390/vaccines12050560 -
Viruses May 2024African Swine Fever Virus (ASFV) is a large dsDNA virus that encodes at least 150 proteins. The complexity of ASFV and lack of knowledge of effector immune functions and...
Identification of an Immunodominant B-Cell Epitope in African Swine Fever Virus p30 Protein and Evidence of p30 Antibody-Mediated Antibody Dependent Cellular Cytotoxicity.
African Swine Fever Virus (ASFV) is a large dsDNA virus that encodes at least 150 proteins. The complexity of ASFV and lack of knowledge of effector immune functions and protective antigens have hindered the development of safe and effective ASF vaccines. In this study, we constructed four Orf virus recombinant vectors expressing individual ASFV genes , -, , and - (ORFV-ASFV-, -, -, and -). All recombinant viruses expressed the heterologous ASFV proteins in vitro. We then evaluated the immunogenicity of the recombinants by immunizing four-week-old piglets. In two independent animal studies, we observed high antibody titers against ASFV p30, encoded by gene. Using Pepscan ELISA, we identified a linear B-cell epitope of 12 amino acids in length (Peptide 15) located in an exposed loop region of p30 as an immunodominant ASFV epitope. Additionally, antibodies elicited against ASFV p30 presented antibody-dependent cellular cytotoxicity (ADCC) activity. These results underscore the role of p30 on antibody responses elicited against ASFV and highlight an important functional epitope that contributes to p30-specific antibody responses.
Topics: African Swine Fever Virus; Animals; Swine; Antibodies, Viral; Epitopes, B-Lymphocyte; Immunodominant Epitopes; African Swine Fever; Antibody-Dependent Cell Cytotoxicity; Viral Proteins; Viral Vaccines
PubMed: 38793639
DOI: 10.3390/v16050758 -
Viruses May 2024Viral infection can regulate the cell cycle, thereby promoting viral replication. Hijacking and altering the cell cycle are important for the virus to establish and...
Viral infection can regulate the cell cycle, thereby promoting viral replication. Hijacking and altering the cell cycle are important for the virus to establish and maintain a latent infection. Previously, Spodoptera exigua multiple nucleopolyhedrovirus (SeMNPV)-latently infected P8-Se301-C1 cells, which grew more slowly than Se301 cells and interfered with homologous SeMNNPV superinfection, were established. However, the effects of latent and superinfection with baculoviruses on cell cycle progression remain unknown. In this study, the cell cycle profiles of P8-Se301-C1 cells and SeMNPV or Autographa californica multiple nucleopolyhedrovirus (AcMNPV)-infected P8-Se301-C1 cells were characterized by flow cytometry. The results showed that replication-related genes , , and were down-regulated ( < 0.05) in P8-Se301-C1 cells, and the S phase of P8-Se301-C1 cells was longer than that of Se301 cells. P8-Se301-C1 cells infected with SeMNPV did not arrest in the G2/M phase or affect the expression of and cyclin-dependent kinase 1 (). Furthermore, when P8-Se301-C1 cells were infected with SeMNPV after synchronized treatment with hydroxyurea and nocodazole, light microscopy and qRT-PCR analysis showed that, compared with unsynchronized cells and S and G2/M phase cells, SeMNPV-infected P8-Se301-C1 cells in G1 phase induced G2/M phase arrest, and the amount of virus adsorption and intracellular viral DNA replication were significantly increased ( < 0.05). In addition, budded virus (BV) production and occlusion body (OB)-containing cells were both increased at 120 h post-infection ( < 0.05). The expression of and was significantly down-regulated at 48 h post-infection ( < 0.05). Finally, the arrest of SeMNPV-infected G1 phase cells in the G2/M phase increased BV production ( < 0.05) and the number of OB-containing cells. In conclusion, G1 phase infection and G2/M arrest are favorable to SeMNPV proliferation in P8-Se301-C1 cells, thereby alleviating the homologous superinfection exclusion. The results contribute to a better understanding of the relationship between baculoviruses and insect cell cycle progression and regulation.
Topics: Animals; Virus Replication; Nucleopolyhedroviruses; Cell Line; Spodoptera; Superinfection; G2 Phase Cell Cycle Checkpoints; G1 Phase
PubMed: 38793618
DOI: 10.3390/v16050736 -
Current Oncology (Toronto, Ont.) May 2024This case report describes the development of Progressive Multifocal Leukoencephalopathy (PML) in a 72-year-old male with relapsed/refractory multiple myeloma (RRMM),...
This case report describes the development of Progressive Multifocal Leukoencephalopathy (PML) in a 72-year-old male with relapsed/refractory multiple myeloma (RRMM), following a single dose of teclistamab amidst a COVID-19 infection. Shortly after starting teclistamab treatment, the patient developed symptoms, including fever, altered mental status, and right-sided paresis. A diagnosis of PML was confirmed through the detection of JC virus PCR in the cerebrospinal fluid. Our report emphasizes the occurrence of PML after only one dose of teclistamab and highlights teclistamab's potential for severe infectious complications, despite its promise in treating RRMM.
Topics: Humans; Leukoencephalopathy, Progressive Multifocal; Multiple Myeloma; Male; Aged; COVID-19; JC Virus; SARS-CoV-2
PubMed: 38785483
DOI: 10.3390/curroncol31050202 -
Journal of Neurovirology May 2024Progressive multifocal leukoencephalopathy (PML) is an opportunistic infectious demyelinating disease of the central nervous system caused by JC polyomavirus...
Progressive multifocal leukoencephalopathy (PML) is an opportunistic infectious demyelinating disease of the central nervous system caused by JC polyomavirus predominantly affecting immunocompromised individuals. Nowadays, HIV, hematological malignancies and iatrogenic immune suppression account for most PML cases. For unknown reasons, spinal cord is classically protected from PML lesions. Here, we report the course of a patient harboring spinal cord lesions in the context of PML with immune reconstitution inflammatory syndrome and review the eight other cases reported in the literature so far. Then, we discuss the evolving spectrum of PML over recent years, potentially making its diagnosis more challenging.
PubMed: 38778006
DOI: 10.1007/s13365-024-01213-y -
Journal of the Neurological Sciences Jun 2024Progressive multifocal leukoencephalopathy (PML) is a potentially life-threatening complication among Multiple Sclerosis (MS) patients under natalizumab treatment, with...
Association of B-cell activating factor gene variants with serum anti-JCV antibody positivity in male patients with multiple sclerosis under natalizumab treatment: Implications for progressive multifocal leukoencephalopathy risk stratification.
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.
Topics: Humans; Natalizumab; B-Cell Activating Factor; Male; Leukoencephalopathy, Progressive Multifocal; Adult; Female; Immunologic Factors; JC Virus; Multiple Sclerosis, Relapsing-Remitting; Middle Aged; Antibodies, Viral; Polymorphism, Single Nucleotide
PubMed: 38761670
DOI: 10.1016/j.jns.2024.123046 -
Multiple Sclerosis and Related Disorders Jul 2024Natalizumab (NAT) pharmacokinetics and pharmacodynamics are complicated by arm exchange with endogenous IgG4, resulting in a mixture of a more potent intact, bivalent...
BACKGROUND
Natalizumab (NAT) pharmacokinetics and pharmacodynamics are complicated by arm exchange with endogenous IgG4, resulting in a mixture of a more potent intact, bivalent form and a less potent, functionally monovalent form. Total NAT and endogenous IgG4 concentrations vary considerably across patients. This study assessed the concentration of intact NAT, and how it relates to total NAT and endogenous IgG4 levels in blood and saliva.
METHODS
Paired serum and saliva samples from a small cohort of relapsing-remitting multiple sclerosis patients were measured for levels of intact NAT, total NAT, IgG and IgG4.
RESULTS
Intact NAT concentration was dependent on both total NAT and endogenous IgG4 levels. Low endogenous IgG4 led to a higher ratio of intact NAT to total NAT, while the opposite was observed in subjects with high endogenous IgG4. Serum and saliva measurements show good concordance.
CONCLUSIONS
Intact NAT concentration is influenced by both NAT pharmacokinetics and endogenous IgG4 levels. Patients with low IgG4 levels can have high concentrations of intact NAT even with lower levels of total NAT, which may explain cases of NAT-associated progressive multifocal leukoencephalopathy (PML) in such patients. Monitoring both forms of NAT could better guide dosing, maximizing drug efficacy and safety.
Topics: Humans; Natalizumab; Multiple Sclerosis, Relapsing-Remitting; Immunoglobulin G; Female; Male; Adult; Immunologic Factors; Saliva; Middle Aged
PubMed: 38759421
DOI: 10.1016/j.msard.2024.105667 -
Circulation Research Jun 2024Calcium (Ca) uptake by mitochondria occurs via the mitochondrial Ca uniporter. Mitochondrial Ca uniporter exists as a complex, regulated by 3 MICU (mitochondrial Ca...
BACKGROUND
Calcium (Ca) uptake by mitochondria occurs via the mitochondrial Ca uniporter. Mitochondrial Ca uniporter exists as a complex, regulated by 3 MICU (mitochondrial Ca uptake) proteins localized in the intermembrane space: MICU1, MICU2, and MICU3. Although MICU3 is present in the heart, its role is largely unknown.
METHODS
We used CRISPR-Cas9 to generate a mouse with global deletion of MICU3 and an adeno-associated virus (AAV9) to overexpress MICU3 in wild-type mice. We examined the role of MICU3 in regulating mitochondrial calcium ([Ca]) in ex vivo hearts using an optical method following adrenergic stimulation in perfused hearts loaded with a Ca-sensitive fluorophore. Additionally, we studied how deletion and overexpression of MICU3, respectively, impact cardiac function in vivo by echocardiography and the molecular composition of the mitochondrial Ca uniporter complex via Western blot, immunoprecipitation, and Blue native-PAGE analysis. Finally, we measured MICU3 expression in failing human hearts.
RESULTS
MICU3 knock out hearts and cardiomyocytes exhibited a significantly smaller increase in [Ca] than wild-type hearts following acute isoproterenol infusion. In contrast, heart with overexpression of MICU3 exhibited an enhanced increase in [Ca] compared with control hearts. Echocardiography analysis showed no significant difference in cardiac function in knock out MICU3 mice relative to wild-type mice at baseline. However, mice with overexpression of MICU3 exhibited significantly reduced ejection fraction and fractional shortening compared with control mice. We observed a significant increase in the ratio of heart weight to tibia length in hearts with overexpression of MICU3 compared with controls, consistent with hypertrophy. We also found a significant decrease in MICU3 protein and expression in failing human hearts.
CONCLUSIONS
Our results indicate that increased and decreased expression of MICU3 enhances and reduces, respectively, the uptake of [Ca] in the heart. We conclude that MICU3 plays an important role in regulating [Ca] physiologically, and overexpression of MICU3 is sufficient to induce cardiac hypertrophy, making MICU3 a possible therapeutic target.
Topics: Animals; Humans; Calcium-Binding Proteins; Mitochondria, Heart; Mice; Myocytes, Cardiac; Mice, Knockout; Male; Mitochondrial Membrane Transport Proteins; Calcium; Cardiomegaly; Mice, Inbred C57BL; Calcium Channels; Calcium Signaling; Heart Failure; Cation Transport Proteins; Female
PubMed: 38747181
DOI: 10.1161/CIRCRESAHA.123.324026 -
Molecular Therapy. Oncology Jun 2024V937 is an investigational, genetically unmodified Kuykendall strain of coxsackievirus A21, which has been evaluated in the clinic for advanced solid tumor malignancies....
V937 is an investigational, genetically unmodified Kuykendall strain of coxsackievirus A21, which has been evaluated in the clinic for advanced solid tumor malignancies. V937 specifically infects and lyses tumor cells that overexpress intercellular adhesion molecule-1 (ICAM-1). Intratumoral V937 as a monotherapy and in combination with anti-PD-1 antibody pembrolizumab has shown clinical response in patients with metastatic melanoma, which overexpresses ICAM-1. Here, we investigate in preclinical studies the potential bidirectional cross-talk between hepatocellular carcinomas (HCC) or colorectal carcinomas (CRC) and immune cells when treated with V937 alone or in combination with pembrolizumab. We show that while V937 treatment of tumor cell lines or organoids or peripheral blood mononuclear cells (PBMCs) alone induced a minimal immunological response, V937 treatment of non-contact co-cultures of tumor cell lines or CRC organoids with PBMCs led to robust production of proinflammatory cytokines and immune cell activation. In addition, both recombinant interferon-gamma and pembrolizumab increased ICAM-1 on tumor cell lines or organoids and, in turn, amplified V937-mediated oncolysis and immunogenicity. These findings provide critical mechanistic insights on the cross-talk between V937-mediated oncolysis and immune responses, demonstrating the therapeutic potential of V937 in combination with PD-1 blockade to treat immunologically quiescent cancers.
PubMed: 38745749
DOI: 10.1016/j.omton.2024.200807 -
Multiple Sclerosis and Related Disorders Jul 2024Natalizumab is an effective treatment for relapsing multiple sclerosis (MS). During therapy, individuals are at increased risk of developing progressive multifocal...
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 1.71×10-1.07×10 international units (IU)/mL detected by RT-PCR, corresponding to 4.62×10-9.85×10 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.
Topics: Humans; JC Virus; Natalizumab; Feces; Adult; Male; Female; Antibodies, Viral; DNA, Viral; Middle Aged; Immunologic Factors; Leukoencephalopathy, Progressive Multifocal; Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis
PubMed: 38735204
DOI: 10.1016/j.msard.2024.105664