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Association between brain cancer immunogenetic profile and in silico immunogenicities of 11 viruses.Scientific Reports Dec 2023Several viruses including human herpes viruses (HHVs), human polyomavirus JCV, and human papilloma virus (HPV) have been implicated in brain cancer, albeit...
Several viruses including human herpes viruses (HHVs), human polyomavirus JCV, and human papilloma virus (HPV) have been implicated in brain cancer, albeit inconsistently. Since human leukocyte antigen (HLA) is centrally involved in the human immune response to viruses and has been implicated in brain cancer, we evaluated in silico the immunogenicity between 69 Class I HLA alleles with epitopes of proteins of 9 HHVs, JCV, and HPV with respect to a population-based HLA-brain cancer profile. We found that immunogenicity varied widely across HLA alleles with HLA-C alleles exhibiting the highest immunogenicity, and that immunogenicity scores were negatively associated with the population-based HLA-brain cancer profile, particularly for JCV, HHV6A, HHV5, HHV3, HHV8, and HHV7. Consistent with the role of HLA in foreign antigen elimination, the findings suggest that viruses with proteins of high HLA immunogenicity are eliminated more effectively and, consequently, less likely to cause brain cancer; conversely, the absence of highly immunogenic HLA may allow the viral antigens to persist, contributing to cancer.
Topics: Humans; Papillomavirus Infections; Immunogenetics; Histocompatibility Antigens Class I; HLA Antigens; Histocompatibility Antigens Class II; JC Virus; Brain Neoplasms; Alleles
PubMed: 38057480
DOI: 10.1038/s41598-023-48843-6 -
Nature Communications Feb 2024Invariant natural killer T (iNKT) cells, a unique T cell population, lend themselves for use as adoptive therapy due to diverse roles in orchestrating immune responses....
Invariant natural killer T (iNKT) cells, a unique T cell population, lend themselves for use as adoptive therapy due to diverse roles in orchestrating immune responses. Originally developed for use in cancer, agenT-797 is a donor-unrestricted allogeneic ex vivo expanded iNKT cell therapy. We conducted an open-label study in virally induced acute respiratory distress syndrome (ARDS) caused by the severe acute respiratory syndrome-2 virus (trial registration NCT04582201). Here we show that agenT-797 rescues exhausted T cells and rapidly activates both innate and adaptive immunity. In 21 ventilated patients including 5 individuals receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO), there are no dose-limiting toxicities. We observe an anti-inflammatory systemic cytokine response and infused iNKT cells are persistent during follow-up, inducing only transient donor-specific antibodies. Clinical signals of associated survival and prevention of secondary infections are evident. Cellular therapy using off-the-shelf iNKT cells is safe, can be rapidly scaled and is associated with an anti-inflammatory response. The safety and therapeutic potential of iNKT cells across diseases including infections and cancer, warrants randomized-controlled trials.
Topics: Humans; Natural Killer T-Cells; Cytokines; Respiratory Distress Syndrome; Neoplasms; Anti-Inflammatory Agents
PubMed: 38321023
DOI: 10.1038/s41467-024-44905-z -
Genes Dec 2023The resistance of silkworms to nuclear polyhedrosis virus (BmNPV) is controlled by a major dominant gene and multiple modifying genes. Given the presence of modified...
The resistance of silkworms to nuclear polyhedrosis virus (BmNPV) is controlled by a major dominant gene and multiple modifying genes. Given the presence of modified genes, it is difficult to determine the main gene by positional cloning. In this study, the main anti-BmNPV gene of BmNPV-resistant silkworm variety N was introduced into the susceptible variety Su to breed the near-isogenic line SuN with BmNPV resistance. The infection process of BmNPV in the hemolymph of Su and SuN was analyzed using the cell analysis system TissueFAXS PLUS. According to the law of infection and proliferation, hemolymph was extracted every 6 h for two-dimensional electrophoresis (2-DE) analysis and quantitative real-time polymerase chain reaction (qRT-PCR). Seven DEPs were found in comparisons between Su and SuN by 2-DE analysis. Among them, acid phosphatase, storage protein, and phenoloxidase can prevent pathogen invasion, which may play a role against BmNPV. Polyamine oxidase plays an important role in energy metabolism, which may be indirectly involved in the process of resisting BmNPV. Most of the transcriptional expression profiles of the seven DEPs were consistent with the 2-DE results. This study can provide a reference for the identification of anti-BmNPV genes and the breeding of BmNPV-resistant silkworm varieties.
Topics: Animals; Bombyx; Nucleopolyhedroviruses; Proteomics; Genes, Dominant
PubMed: 38254949
DOI: 10.3390/genes15010059 -
Cancers Oct 2023Chimeric antigen receptor T cell (CAR-T) therapy has been applied in the treatment of B-cell lymphoma; however, CAR-T manufacturing requires virus- or non-virus-based...
Chimeric antigen receptor T cell (CAR-T) therapy has been applied in the treatment of B-cell lymphoma; however, CAR-T manufacturing requires virus- or non-virus-based genetic modification, which causes high manufacturing costs and potential safety concerns. Antibody-cell conjugation (ACC) technology, which originated from bio-orthogonal click chemistry, provides an efficient approach for arming immune cells with cancer-targeting antibodies without genetic modification. Here, we applied ACC technology in Vγ9Vδ2 T (γδ2 T) cells to generate a novel off-the-shelf CD20-targeting cell therapy ACE1831 (rituximab-conjugated γδ2 T cells) against relapsed/refractory B-cell lymphoma. ACE1831 exhibited superior cytotoxicity against B-cell lymphoma cells and rituximab-resistant cells compared to γδ2 T cells without rituximab conjugation. The in vivo xenograft study demonstrated that ACE1831 treatment strongly suppressed the aggressive proliferation of B-cell lymphoma and prolonged the survival of tumor-bearing mice with no observed toxicity. Mass spectrometry analysis indicated that cell activation receptors including the TCR complex, integrins and cytokine receptors were conjugated with rituximab. Intriguingly, the antigen recognition of the ACC-linked antibody/receptor complex stimulated NFAT activation and contributed to ACE1831-mediated cytotoxicity against CD20-expressing cancer cells. This study elucidates the role of the ACC-linked antibody/receptor complex in cytotoxicity and supports the potential of ACE1831 as an off-the-shelf γδ2 cell therapy against relapsed/refractory B-cell lymphoma.
PubMed: 37835538
DOI: 10.3390/cancers15194844 -
Clinical Infectious Diseases : An... Jul 2023Low-barrier care (LBC) for people with human immunodeficiency virus (HIV) is a differentiated service delivery strategy to engage people in HIV treatment who are not... (Review)
Review
Low-barrier care (LBC) for people with human immunodeficiency virus (HIV) is a differentiated service delivery strategy to engage people in HIV treatment who are not well-engaged in conventionally organized HIV medical care. The LBC approach is flexible, but experience suggests that the intervention has distinct core components. This review summarizes our experience implementing one model of LBC, the Max Clinic in Seattle; describes the core components of the intervention; and presents a framework for implementing low-barrier HIV care with the goal of providing a practical guide for clinical and public health leaders seeking to implement a new LBC program. A systematic approach to addressing key factors during LBC implementation can support practitioners to design an LBC approach that fits the local context while maintaining essential elements of the intervention.
Topics: Humans; HIV Infections; HIV; Public Health
PubMed: 37021670
DOI: 10.1093/cid/ciad202 -
Frontiers in Veterinary Science 2024Transmissible gastroenteritis virus (TGEV) could cause diarrhea, vomiting, dehydration and even death in piglets, miRNA played an important role in the interaction...
Transmissible gastroenteritis virus (TGEV) could cause diarrhea, vomiting, dehydration and even death in piglets, miRNA played an important role in the interaction between virus and cell. The study aimed to investigate the impact of miR-17 on the polysaccharide of Polygonum Cillinerve (PCP) in combating TGEV. miR-17 was screened and transfection validation was performed by Real-time PCR. The function of miR-17 on PK15 cells infected with TGEV and treated with PCP was investigated by DCFH-DA loading probe, JC-1 staining and Hoechst fluorescence staining. Furthermore, the effect of miR-17 on PCP inhibiting TGEV replication and apoptosis signaling pathways during PCP against TGEV infection was measured through Real-time PCR and Western blot. The results showed that miR-17 mimic and inhibitor could be transferred into PK15 cells and the expression of miR-17 significantly increased and decreased respectively compared with miR-17 mimic and inhibitor ( < 0.05). A total 250 μg/mL of PCP could inhibit cells apoptosis after transfection with miR-17. PCP (250 μg/mL and 125 μg/mL) significantly inhibited the decrease in mitochondrial membrane potential induced by TGEV after transfection with miR-17 ( < 0.05). After transfection of miR-17 mimic, PCP at concentrations of 250 μg/mL and 125 μg/mL significantly promoted the mRNA expression of P53, cyt C and caspase 9 ( < 0.05). Compared with the control group, the replication of TGEV gRNA and gene N was significantly inhibited by PCP at concentrations of 250 μg/mL and 125 μg/mL after transfection of both miR-17 mimic and inhibitor ( < 0.05). PCP at 62.5 μg/mL significantly inhibited the replication of gene S following transfection with miR-17 inhibitor ( < 0.05). These results suggested that PCP could inhibit the replication of TGEV and apoptosis induced by TGEV by regulating miR-17.
PubMed: 38444776
DOI: 10.3389/fvets.2024.1360102 -
Journal of Cancer Research and Clinical... Sep 2023Even in the novel immunotherapy era, Merkel cell carcinoma (MCC) remains challenging in its treatment. Apart from Merkel cell polyomavirus (MCPyV) associated MCC, this...
BACKGROUND
Even in the novel immunotherapy era, Merkel cell carcinoma (MCC) remains challenging in its treatment. Apart from Merkel cell polyomavirus (MCPyV) associated MCC, this cancer is linked in about 20% of cases to ultraviolet-induced mutational burden frequently causing aberrations in Notch and PI3K/AKT/mTOR signalling pathways. The recently developed agent GP-2250 is capable to inhibit growth of cells of different cancers, including pancreatic neuroendocrine tumors. The objective of the present study was to investigate the effects of GP-2250 on MCPyV-negative MCC cells.
METHODS
Methods We employed three cell lines (MCC13, MCC14.2, MCC26) which were exposed to different GP-2250doses. GP-2250's effects on cell viability, proliferation, and migration were evaluated by means of MTT, BrdU, and scratch assays, respectively. Flow cytometry was performed for the evaluation of apoptosis and necrosis. Western blotting was implemented for the determination of AKT, mTOR, STAT3, and Notch1 protein expression.
RESULTS
Cell viability, proliferation, and migration decreased with increasing GP-2250 doses. Flow cytometry revealed a dose response to GP-2250 in all three MCC cell lines. While the viable fraction decreased, the share of necrotic and in a smaller amount the apoptotic cells increased. Regarding Notch1, AKT, mTOR, and STAT3 expression a comparatively time- and dose-dependent decrease of protein expression in the MCC13 and MCC26 cell lines was observed. By contrast, Notch1, AKT, mTOR, and STAT3 expression in MCC14.2 was scarcely altered or even increased by the three dosages of GP-2250 applied.
CONCLUSIONS
The present study indicates GP-2250 having anti-neoplastic effects in MCPyV-negative tumor cells in regard to viability, proliferation, and migration. Moreover, the substance is capable of downregulating protein expression of aberrant tumorigenic pathways in MCPyV-negative MCC cells.
Topics: Humans; Carcinoma, Merkel Cell; Skin Neoplasms; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Merkel cell polyomavirus; TOR Serine-Threonine Kinases; Antineoplastic Agents
PubMed: 37311987
DOI: 10.1007/s00432-023-04960-3 -
Nature Communications Apr 2024Cross-reactive antibodies with Fc receptor (FcR) effector functions may mitigate pandemic virus impact in the absence of neutralizing antibodies. In this exploratory... (Randomized Controlled Trial)
Randomized Controlled Trial
Cross-reactive antibodies with Fc receptor (FcR) effector functions may mitigate pandemic virus impact in the absence of neutralizing antibodies. In this exploratory study, we use serum from a randomized placebo-controlled trial of seasonal trivalent influenza vaccination in children (NCT00792051) conducted at the onset of the 2009 H1N1 pandemic (pH1N1) and monitored for infection. We found that seasonal vaccination increases pH1N1 specific antibodies and FcR effector functions. Furthermore, prospective baseline antibody profiles after seasonal vaccination, prior to pH1N1 infection, show that unvaccinated uninfected children have elevated ADCC effector function, FcγR3a and FcγR2a binding antibodies to multiple pH1N1 proteins, past seasonal and avian (H5, H7 and H9) strains. Whereas, children that became pH1N1 infected after seasonal vaccination have antibodies focussed to seasonal strains without FcR functions, and greater aggregated HA-specific profiles for IgM and IgG3. Modeling to predict infection susceptibility, ranked baseline hemagglutination antibody inhibition as the highest contributor to lack of pH1N1 infection, in combination with features that include pH1-IgG1, H1-stem responses and FcR binding to seasonal vaccine and pH1 proteins. Thus, seasonal vaccination can have benefits against pandemic influenza viruses, and some children already have broadly reactive antibodies with Fc potential without vaccination and may be considered 'elite influenza controllers'.
Topics: Child; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Prospective Studies; Antibodies, Viral; Antibodies, Neutralizing; Immunoglobulin G; Influenza Vaccines
PubMed: 38615070
DOI: 10.1038/s41467-024-47590-0 -
The Lancet. Global Health Mar 2024The first randomised controlled trial of single-dose human papillomavirus (HPV) vaccine efficacy, the Kenya single-dose HPV-vaccine efficacy (KEN SHE) trial, showed...
Comparing one dose of HPV vaccine in girls aged 9-14 years in Tanzania (DoRIS) with one dose in young women aged 15-20 years in Kenya (KEN SHE): an immunobridging analysis of randomised controlled trials.
BACKGROUND
The first randomised controlled trial of single-dose human papillomavirus (HPV) vaccine efficacy, the Kenya single-dose HPV-vaccine efficacy (KEN SHE) trial, showed greater than 97% efficacy against persistent HPV16 and HPV18 infection at 36 months among women in Kenya. We compared antibody responses after one dose of HPV vaccine in the Dose Reduction Immunobridging and Safety Study (DoRIS), the first randomised trial of the single- dose regimen in girls aged 9-14 years, the target age range for vaccination, with those after one dose of the same vaccine in KEN SHE.
METHODS
In the DoRIS trial, 930 girls aged 9-14 years in Tanzania were randomly assigned to one, two, or three doses of the 2-valent vaccine (Cervarix) or the 9-valent vaccine (Gardasil-9). The proportion seroconverting and geometric mean concentrations (GMCs) at month 24 after one dose were compared with those in women aged 15-20 years who were randomly assigned to one dose of the same vaccines at the same timepoint in KEN SHE. Batched samples were tested together by virus-like particle ELISA for HPV16 and HPV18 IgG antibodies. Non-inferiority of GMC ratios (DoRIS trial:KEN SHE) was predefined as a lower bound of the 95% CI less than 0·50.
FINDINGS
Month 24 HPV16 and HPV18 antibody GMCs in DoRIS were similar or higher than those in KEN SHE. 2-valent GMC ratios were 0·90 (95% CI 0·72-1·14) for HPV16 and 1·02 (0·78-1·33) for HPV18. 9-valent GMC ratios were 1·44 (95% CI 1·14-1·82) and 1·47 (1·13-1·90), respectively. Non-inferiority of antibody GMCs and seropositivity was met for HPV16 and HPV18 for both vaccines.
INTERPRETATION
HPV16 and HPV18 immune responses in young girls 24 months after a single dose of 2-valent or 9-valent HPV vaccine were comparable to those in young women who were randomly assigned to a single dose of the same vaccines and in whom efficacy had been shown. A single dose of HPV vaccine, when given to girls in the target age range for vaccination, induces immune responses that could be effective against persistent HPV16 and HPV18 infection at least two years after vaccination.
FUNDING
The UK Department of Health and Social Care, the Foreign, Commonwealth, & Development Office, the Global Challenges Research Fund, the UK Medical Research Council and Wellcome Trust Joint Global Health Trials scheme, the Bill and Melinda Gates Foundation, the US National Cancer Institute; the US National Institutes of Health, and the Francis and Dorothea Reed Endowed Chair in Infectious Diseases.
TRANSLATION
For the KiSwahili translation of the abstract see Supplementary Materials section.
Topics: Female; Humans; Antibodies, Viral; Papillomavirus Infections; Tanzania; Drug Tapering; Kenya; Papillomavirus Vaccines; Human papillomavirus 16; Human papillomavirus 18; Randomized Controlled Trials as Topic
PubMed: 38365419
DOI: 10.1016/S2214-109X(23)00586-7 -
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