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

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小鼠的人乳头瘤病毒 (HPV) 感染模型，并支持新型 HPV 疫苗开发的转化研究需要动物模型。它们是人类病理学的有力表征，可以用来测试具有临床重要性的问题，以及为开发新的干预措施和 HPV 患者利益提供可靠的信息是首要的。全世界至少 5% 的癌症的病因，主要是宫颈癌和其他癌症的子集不幸的是，没有具体的癌症。抗病毒疗法，但基于疫苗的方法非常有希望。临床上的治疗性 HPV 疫苗，包括我们的 pNGLV4aCRTE6E7L2 DNA，但迄今为止，还没有尽管疫苗在当前标准动物身上的数据有希望，但在治疗患者方面取得的成功有限这表明需要更具预测性的动物模型尚未完成其生命周期。并在小鼠或细胞培养单层中产生病毒粒子，从而产生 HPV 假病毒粒子，从而传递报告基因该系统并不完全模拟病毒衣壳的组装和成熟。表达 E4 的分化上皮或提供产生疾病的模型。因此，我们需要在乳头状瘤中产生并表达临床相关 HPV 序列的病毒。提议通过整合关键 HPV 来改变小家鼠乳头瘤病毒 1 型 (MmuPV1) 的用途序列并证明其可用作测试新型治疗性和保护性 HPV 疫苗的模型。具体目标 1：开发包含 HPV 序列的 MmuPV1 病毒。 (OTR) 和 HIV+ 患者表现出更严重和进展性的 HPV 疾病，并且感染率显着更高免疫受损患者中的 HPV 相关恶性肿瘤（NMSC）是非黑色素瘤皮肤癌。与最初在疣状表皮发育不良 (EDV) 中描述的大量 βHPV 相关具体目标 2：开发基于 MmuPV1 的人类群体小鼠攻击模型。验证这些新小鼠患 HPV 相关癌症的正常风险和高风险。 HPV 感染和疾病模型，我们建议检查一种已获得许可的 HPV 疫苗和两种疫苗的功效我们的临床级实验疫苗即将进入早期阶段测试：RG1-VLP，一种单一病毒样疫苗旨在提供针对不同 HPV 类型的广泛免疫力的颗粒抗原，以及候选治疗方法 DNA 疫苗 pNGLV4aCRTE6E7L2 通过电穿孔施用具体目标 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和 HPV 相关癌症高风险受试者的小鼠模型中的终点。