Mouse modeling of HPV infection

HPV感染的小鼠模型

基本信息

批准号：
10304917
负责人：
Chien-Fu Hung
金额：
$ 58.26万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10304917
关键词：
3-Dimensional Adherent Culture Animal Model Animals Anogenital cancer Anogenital venereal warts Antibodies Antigen Targeting Antigens Antiviral Therapy Anus C57BL/6 Mouse CD4 Positive T Lymphocytes Canis familiaris Capsid Carcinoma in Situ Cattle Cell Culture Techniques Cell Line Cervical Clinic Clinical Cutaneous DNA DNA Vaccines Data Development Disease Electroporation Epidermodysplasia Verruciformis Epithelial Etiology Exhibits Gardasil Genetic Goals HIV HPV-High Risk Head and Neck Cancer High grade dysplasia House mice Human Papilloma Virus Vaccine Human Papilloma Virus-Related Malignant Neoplasm Human Papillomavirus Human Pathology Human papilloma virus infection Human papillomavirus 16 Human papillomavirus 18 Human papillomavirus 6 Human papillomavirus HPV L1 protein Immune Immunity Immunocompetent Immunologics Immunosuppressive Agents Inbred Mouse India Infection Inherited Intervention Knock-out Laboratory mice Life Cycle Stages Malignant Neoplasms Malignant Squamous Cell Neoplasm Malignant neoplasm of cervix uteri Modeling Mucous Membrane Mus Nude Mice Oral cavity Oryctolagus cuniculus Papilloma Papillomavirus Patients Phase Population Preventive vaccine Prophylactic treatment Public Health Reagent Reporter Research Personnel Risk Site Skin Carcinoma Skin Papilloma Squamous cell carcinoma System Tail Testing Therapeutic Therapeutic Studies Translational Research UV Radiation Exposure Ultraviolet Rays Vaccinated Vaccination Vaccines Vagina Viral Virion Virus Virus Diseases Virus-like particle base carcinogenesis carcinogenicity clinically relevant cohort comparative efficacy cost efficacy evaluation follow-up high risk human model immune resistance immunogenicity mouse model neonate neoplastic cell novel novel therapeutics novel vaccines organ transplant recipient prevent protective efficacy screening success therapeutic candidate tool tumor tumorigenesis vaccine response vaccine trial

3-Dimensional Adherent Culture Animal Model Animals Anogenital cancer Anogenital venereal warts Antibodies Antigen Targeting Antigens Antiviral Therapy Anus C57BL/6 Mouse CD4 Positive T Lymphocytes Canis familiaris Capsid Carcinoma in Situ Cattle Cell Culture Techniques Cell Line Cervical Clinic Clinical Cutaneous DNA DNA Vaccines Data Development Disease Electroporation Epidermodysplasia Verruciformis Epithelial Etiology Exhibits Gardasil Genetic Goals HIV HPV-High Risk Head and Neck Cancer High grade dysplasia House mice Human Papilloma Virus Vaccine Human Papilloma Virus-Related Malignant Neoplasm Human Papillomavirus Human Pathology Human papilloma virus infection Human papillomavirus 16 Human papillomavirus 18 Human papillomavirus 6 Human papillomavirus HPV L1 protein Immune Immunity Immunocompetent Immunologics Immunosuppressive Agents Inbred Mouse India Infection Inherited Intervention Knock-out Laboratory mice Life Cycle Stages Malignant Neoplasms Malignant Squamous Cell Neoplasm Malignant neoplasm of cervix uteri Modeling Mucous Membrane Mus Nude Mice Oral cavity Oryctolagus cuniculus Papilloma Papillomavirus Patients Phase Population Preventive vaccine Prophylactic treatment Public Health Reagent Reporter Research Personnel Risk Site Skin Carcinoma Skin Papilloma Squamous cell carcinoma System Tail Testing Therapeutic Therapeutic Studies Translational Research UV Radiation Exposure Ultraviolet Rays Vaccinated Vaccination Vaccines Vagina Viral Virion Virus Virus Diseases Virus-like particle base carcinogenesis carcinogenicity clinically relevant cohort comparative efficacy cost efficacy evaluation follow-up high risk human model immune resistance immunogenicity mouse model neonate neoplastic cell novel novel therapeutics novel vaccines organ transplant recipient prevent protective efficacy screening success therapeutic candidate tool tumor tumorigenesis vaccine response vaccine trial

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项目摘要

SUMMARY Our overall goal is to create a laboratory mouse-based model of human papillomavirus (HPV) infection and disease to support the development of novel HPV vaccines. Translational research requires animal models that are robust representations of human pathology in which to test questions of clinical importance, and provide reliable information for the development of novel interventions and patient benefit. HPV is the primary etiologic agent of at least 5% of all cancers worldwide, mostly cervical and subsets of other anogential and head and neck cancers and potentially also non-melanoma skin cancers. Unfortunately, there is no specific antiviral therapy, but vaccine-based approaches are very promising. Many groups are bringing candidate therapeutic HPV vaccines to the clinic, including our pNGLV4aCRTE6E7L2 DNA, but to date there has been limited success in treating patients despite promising data with the vaccines in the current standard animal models. This demonstrates the need for more predictive animal models. HPV does not complete its life cycle and produce virions in mice or in cell culture monolayers and so HPV pseudovirions delivering a reporter construct are often used. This system does not fully mimic the assembly and maturation of the viral capsid in E4-expressing differentiating epithelium or provide a disease endpoint. A model that produces disease from virus produced in a papilloma and expressing clinically-relevant HPV sequences is required. Therefore, we propose to transform the utility of Mus musculus papillomavirus type 1 (MmuPV1) by incorporating key HPV sequences and credential it for use as a model for testing novel therapeutic and protective HPV vaccines. SPECIFIC AIM 1: To develop MmuPV1 viruses incorporating HPV sequences. Organ transplant recipients (OTRs) and HIV+ patients exhibit more severe and progressive HPV disease, and dramatically higher rates of HPV-associated malignancies. Non-melanoma skin cancers (NMSC) in immune-compromised patients are associated with a plethora of βHPVs that were initially described in epidermodysplasia verruciformis (EDV) patients. SPECIFIC AIM 2: To develop an MmuPV1-based mouse challenge model of human cohorts at normal and high risk for the development of HPV-associated cancer. To validate these new murine models of HPV infection and disease we propose to examine the efficacy of a licensed HPV vaccine and two of our clinical grade experimental vaccines that will shortly enter early phase testing: RG1-VLP, a single virus-like particle antigen intended to provide broad immunity against diverse HPV types, and the candidate therapeutic DNA vaccine pNGLV4aCRTE6E7L2 administered via electroporation. SPECIFIC AIM 3: To compare the efficacy of the Gardasil 9, pNGLV4aCRTE6E7L2 DNA and RG1-VLP vaccines against disease and viral endpoints in murine models of healthy subjects and those at high risk for HPV-related cancer.

概括我们的总体目标是创建一个基于实验室的人乳头瘤病毒（HPV）感染的模型疾病支持新型HPV疫苗的发展。翻译研究需要动物模型这是人类病理的强大表示，其中测试临床重要性问题，并且提供可靠的信息，以开发新的干预措施和患者福利。 HPV是主要的全球所有癌症中至少有5％的病因学剂，主要是其他闭合性的宫颈和子集头部和颈部癌症以及潜在的非黑色素瘤皮肤癌。不幸的是，没有具体的抗病毒疗法，但是基于疫苗的方法是非常有希望的。许多团体正在带来候选人诊所的治疗性HPV疫苗，包括我们的PNGLV4ACRTE6E7L2 DNA，但迄今已有在当前标准动物中使用疫苗治疗患者目的地有希望数据的成功有限型号。这表明需要更具预测性动物模型。 HPV无法完成其生命周期并在小鼠或细胞培养单层中产生病毒构造经常使用。该系统无法完全模仿病毒capsid的组装和成熟表达E4的区分上皮或提供疾病终点。一种产生疾病的模型需要在乳头状瘤和表达与临床上相关的HPV序列中产生的病毒。因此，我们通过合并关键的HPV来改变Mus Musculus乳头瘤病毒1（MMUPV1）的效用的提议序列和凭证作为用于测试新型治疗和受保护的HPV疫苗的模型。特定目的1：开发结合HPV序列的MMUPV1病毒。器官移植受者（OTRS）和HIV+患者暴露了更严重和进行性的HPV疾病，并且率较高 HPV相关的恶性肿瘤。免疫功能低下的患者的非黑色素瘤皮肤癌（NMSC）是与大量的βHPV相关，这些βHPV最初在表皮发育不良中描述（EDV）患者。特定目的2：开发基于MMUPV1的小鼠挑战模型 HPV相关癌症发展的正常和高风险。验证这些新鼠 HPV感染和疾病模型我们建议检查许可的HPV疫苗的效率和两种我们的临床级实验疫苗将很快进入早期测试：RG1-VLP，一种单个病毒样颗粒抗原旨在为潜水员HPV类型提供广泛的免疫力和候选治疗通过电穿孔给药的DNA疫苗PNGLV4ACRTE6E7L2。特定目标3：比较 Gardasil 9，PNGLV4ACRTE6E7L2 DNA和RG1-VLP疫苗针对疾病和病毒的功效健康受试者的鼠模型和HPV相关癌症风险高的终点。