Present Homologous and Heterologous Antigen with Hepatitis E Virus

戊型肝炎病毒存在同源和异源抗原

• 批准号: 8507842
• 负责人: R.Holland Cheng
• 金额: $ 38.49万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507842
• 关键词: Acute; Acute Hepatitis; Adenoviruses; Adhesions; Adult; Amino Acids; Animals; Antibodies; Antibody Binding Sites; Antigen Presentation; Antigens; Attenuated; Binding; Binding Sites; Capsid Proteins; Carcinogens; Cells; Chronic; Chronic Hepatitis; Chronic Hepatitis B; Clinical; Collaborations; Complex; Cryoelectron Microscopy; Cytotoxic T-Lymphocytes; DNA; DNA Vaccines; DNA delivery; Data; Dendritic Cells; Disease; Encapsulated; Enteral; Enzymes; Epithelium; Epitopes; Fab Immunoglobulins; Gastrointestinal tract structure; Gene Delivery; Gene Targeting; Genes; Genetic Transcription; Genotype; Goals; HIV; HIV Envelope Protein gp120; Hand; Health; Hepatitis B; Hepatitis B Vaccines; Hepatitis B Virus; Hepatitis E virus; Hepatocyte; Hereditary Disease; Heterophile Antigens; Homing; Human; Human Genetics; Image; Immune response; Immune system; Immunity; Immunoglobulin A; Immunologic Surveillance; Immunosorbents; In Vitro; Individual; Infection; Insecta; Intestines; Kinetics; Ligands; Link; Liver; Liver Failure; Location; M cell; Mediating; Modeling; Mucosal Immune Responses; Mucosal Immunity; Oral; Oral Administration; Patients; Peptides; Phase; Play; Procedures; Production; Proteins; Recombinants; Reporting; Research; Retroviridae; Risk; Role; Route; Safety; Specificity; Structure; Surface; Surface Antigens; Surface Plasmon Resonance; T-Lymphocyte; Techniques; Tertiary Protein Structure; Therapeutic; Transportation; Tumor Necrosis Factor-Beta; Vaccination; Vaccines; Viral; Virion; Virus; Virus Diseases; Virus-like particle; Walkers; Water; base; cytokine; design; drug discovery; exhaust; feeding; flexibility; gastrointestinal; gene therapy; image reconstruction; interest; particle; plasmid DNA; prophylactic; reconstruction; research study; response; therapeutic gene; trafficking; uptake; vaccine development

DESCRIPTION (provided by applicant): Advantages of DNA vaccines including well-tolerance, safety and ability to induce antibody, cytotoxic T- lymphocytes, and T-helper immune responses make it more and more attractive in treatment of chronic virus infections. In order to successfully induce immune response, DNA vaccine needs to enter target cell for transcription and subsequent protein production. An ideal delivery carrier needs to be safe and effective in targeting specific cell, provide sufficient protection of DNA plasmid during transportation, as wel as low- responses to any existing self-immunity. Deficient viral particles, such as adenoviruses or retroviruses, offer an attractive option with great benefits in targeting and protection but majr drawbacks on strong self-immunity as well as the complexity in producing recombinant viral particles. Non-replicating virus-like particle derived from human hepatitis E virus (HEV-VLP) is empty icosahedral cage composed of 60 copies of recombinant HEV capsid proteins. This VLP is capable of encapsulating DNA vaccine in vitro, delivering DNA vaccine to epithelium cell at gastrointestinal tract, and inducing antigen-specific humoral and cellular immune responses. The simple procedure in DNA encapsulation makes HEV-VLP of particular interest as gene carrier; however, induction of self-immunity is still the hurdle in using HEV-VLP for therapeutical vaccination. Our studies on HEV-VLP crystal structure and antigenic structure reveal a structural modularity, with which HEV recombinant capsid proteins interplay between VLP assembly and antigen presentation. By carrying insertion of 15 amino acids at an antibody-binding site, the chimeric VLP reduces the reactivity to anti-HEV antibodies meanwhile retains the icosahedral assembly. This data suggests us a strategy to lower the reactivity of VLP to antibody- induced neutralization by structural alteration at antibody-binding sites, a mechanism that viruses have evolved to mediate their escape from host immune surveillance. The proposed experiments in this application include 1) using cryo-electron microscopy and image reconstruction to identify HEV-VLP surface flexible loops that critical to antibody interactions; 2 inserting short peptide into the identified surface loops to create chimeric VLP with attenuate reactivity to HEV-VLP; 3) both wild type and chimeric VLPs will be evaluated in delivery of DNA vaccine encoding the surface antigen of hepatitis B virus, as potential gene carrier for treatment of chronic progressive hepatitis B. Because HEV is an enteric transmitted virus, HEV-VLP is able to transcytose the mucosal barrier at gastrointestinal tract and target specific mucosal region for antigen production. When a short peptide bearing mucosal adhesion ligand is inserted into surface antigenic loops, the chimeric VLP is hypothesized to have strong specificity in targeting mucosal region, leading to potent induction of mucosal immunity. In collaboration with Dr Kit Lam and Dr Christopher Walker, two experts respectively in drug discovery and HBV vaccine development, we expect to obtain sufficient data leading us to repeated use of HEV-VLPs as carrier for clinical gene therapy.

简介（申请人提供）：DNA疫苗具有耐受性好、安全性好、能诱导抗体、细胞毒性T淋巴细胞和T辅助免疫反应等优点，在慢性病毒感染的治疗中越来越有吸引力。为了成功诱导免疫应答，DNA疫苗需要进入靶细胞进行转录和随后的蛋白质生产。理想的递送载体需要安全有效地靶向特定细胞，在运输过程中对DNA质粒提供足够的保护，并且对任何现有的自身免疫反应低。缺陷病毒颗粒，如腺病毒或逆转录病毒，提供了一个有吸引力的选择，在靶向和保护方面有很大的好处，但在强自身免疫和生产重组病毒颗粒的复杂性方面存在重大缺陷。来自人戊型肝炎病毒的非复制病毒样颗粒（HEV- vlp）是由60拷贝重组戊型肝炎病毒衣壳蛋白组成的空二十面体笼。该VLP能够在体外包封DNA疫苗，将DNA疫苗递送至胃肠道上皮细胞，并诱导抗原特异性的体液和细胞免疫反应。DNA包封过程简单，使得HEV-VLP作为基因载体受到特别关注；然而，诱导自身免疫仍然是利用HEV-VLP进行治疗的障碍

项目成果

Chimeric hepatitis E virus-like particle as a carrier for oral-delivery.

• DOI: 10.1016/j.vaccine.2012.10.073
• 发表时间: 2013-01-02
• 期刊: Vaccine
• 影响因子: 5.5
• 作者: Jariyapong P;Xing L;van Houten NE;Li TC;Weerachatyanukul W;Hsieh B;Moscoso CG;Chen CC;Niikura M;Cheng RH
• 通讯作者: Cheng RH

Calpains promote α2β1 integrin turnover in nonrecycling integrin pathway.

• DOI: 10.1091/mbc.e11-06-0548
• 发表时间: 2012-02
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Rintanen N;Karjalainen M;Alanko J;Paavolainen L;Mäki A;Nissinen L;Lehkonen M;Kallio K;Cheng RH;Upla P;Ivaska J;Marjomäki V
• 通讯作者: Marjomäki V

Determining of canine position by multiple facial landmarks to achieve natural esthetics in complete denture treatment.

• DOI: 10.1016/j.prosdent.2020.11.022
• 发表时间: 2022-06
• 期刊: The Journal of prosthetic dentistry
• 作者: Srimaneekarn N;Arayapisit T;Pooktuantong O;Cheng HR;Soonsawad P
• 通讯作者: Soonsawad P

Compensation of missing wedge effects with sequential statistical reconstruction in electron tomography.

• DOI: 10.1371/journal.pone.0108978
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Paavolainen L;Acar E;Tuna U;Peltonen S;Moriya T;Soonsawad P;Marjomäki V;Cheng RH;Ruotsalainen U
• 通讯作者: Ruotsalainen U

Permeability changes of integrin-containing multivesicular structures triggered by picornavirus entry.

• DOI: 10.1371/journal.pone.0108948
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Soonsawad P;Paavolainen L;Upla P;Weerachatyanukul W;Rintanen N;Espinoza J;McNerney G;Marjomäki V;Cheng RH
• 通讯作者: Cheng RH