Molecular pathogenesis and host response following persistent E6/E7 expression

E6/E7 持续表达后的分子发病机制和宿主反应

• 批准号: 8619069
• 负责人: Chien-Fu Hung
• 金额: $ 20.25万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-08 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8619069
• 关键词: Animal Model; Anogenital Human Papilloma Virus Infection; Antigens; Antiviral Agents; Anus; Anxiety; Biological; Biological Process; C57BL/6 Mouse; Cancerous; Cervix Uteri; Chronic; DNA; Data; Development; Disease; Event; Frequencies; Generations; Genes; Genital Human Papilloma Virus Infection; HPV-High Risk; Histopathology; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Immune; Immune response; Immunocompetent; Immunocompromised Host; Immunosuppression; Individual; Infection; Intervention; Intraepithelial Neoplasia; Kinetics; Lesion; Luciferases; Malignant - descriptor; Malignant Neoplasms; Malignant Vaginal Neoplasm; Malignant neoplasm of anus; Malignant neoplasm of vulva; Mediating; Methodology; Modeling; Molecular; Morbidity - disease rate; Mus; Oncogenes; Oncogenic; Operative Surgical Procedures; Pathogenesis; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Premalignant; Proteins; Public Health; Recurrence; Research; Risk; Severities; Sexually Transmitted Diseases; Staging; System; T-Lymphocyte; Testing; Therapeutic; Vaccination; Vagina; Vulva; adaptive immunity; base; carcinogenesis; cell mediated immune response; effective therapy; immunosuppressed; innovation; insight; intraepithelial; non-invasive imaging; novel; public health relevance; ras Oncogene; screening; young man; young woman

PROJECT SUMMARY/ABSTRACT Human papillomavirus (HPV) is the most common sexually transmitted infection. Persistent HPV infection is prevalent in young men and women and infection with a high-risk HPV type, especially HPV-16, is associated with an increased risk of developing an intraepithelial neoplasia. Furthermore, immunosuppressed individuals have a greater risk of being infected with HPV and subsequently developing HPV-associated precancer and cancer lesions. Currently, there is no antiviral treatment for persistent genital HPV infection. The current management for such patients only includes repeat screening for the development precancer and cancer lesions, which generates significant discomfort and anxiety. Furthermore, 90% of all HPV-associated vaginal, vulval and anal cancers are attributable to HPV-16. Additionally, while surgical treatment is quite effective for precancer and early cancer lesions of the cervix, it is associated with significant morbidity and high recurrence rates in vaginal, vulval and anal intraepithelial lesions. Thus, there is an urgent need to develop an innovative treatment to eliminate persistent, high-risk HPV infections, especially HPV-16, in the vagina, vulva and anus. In order to develop an effective treatment for persistent HPV-16 infection and HPV-16-associated anogenital lesions, it is essential to develop a preclinical model of chronic HPV infection. It is now clear that high-risk HPV E6 and E7 oncogenic proteins are responsible for the malignant progression of HPV-associated lesions. We recently generated an HPV-16 pseudovirion (psV) carrying a DNA construct capable of expressing luciferase, HPV E6 and E7 oncogenes and Ras oncogene individually. We found that mice infected with this HPV-16 psV persistently expressed luciferase as well as E6 and E7 oncogenes 150 days after infection of the vagina. In comparison, HPV-16 psV carrying control DNA with luciferase only demonstrated transient expression of the encoded gene. Thus, we have created a non-invasive imaging system to follow the persistent expression of E6/E7 in the vagina. The purpose of the current project is to characterize whether the animal model resembles persistent anogenital HPV infection and to investigate the molecular pathogenesis and immune responses as persistent infection progresses to precancer and cancer lesions. Our specific aims are to: (1) characterize the molecular pathogenesis of persistent HPV-16 E6/E7 and Ras expression in the vagina, vulva and anus of immunocompetent and immunocompromised hosts and (2) characterize E6 and E7-specific humoral and cell- mediated immune responses following persistent anogenital infection with HPV-16 psVs. The successful implementation of this project will generate a preclinical model of persistent HPV-16 E6/E7 expression, resembling chronic high risk HPV infection. This will represent a truly innovative methodology that may change the paradigm in HPV research. Additionally, our preclinical model will facilitate the development of molecular interventions targeting E6/E7 oncogenic proteins for the control of HPV-associated diseases. The results of this study will have significant implications for the management and treatment of persistent HPV infection.

项目摘要/摘要 人乳头瘤病毒（HPV）是最常见的性传播感染。持续的HPV感染是 与高风险HPV类型（尤其是HPV-16）相关的年轻男性和女性以及感染的年轻男性和感染是相关的 随着发生上皮内肿瘤的风险增加。此外，免疫抑制的个体 患有HPV感染并随后开发与HPV相关的预科剂的风险更大 癌症病变。当前，尚无抗病毒药物治疗持续的生殖器HPV感染。电流 此类患者的管理仅包括重复筛查开发前癌和癌症 病变，会产生明显的不适和焦虑。此外，所有与HPV相关的阴道中的90％， 外阴和肛门癌归因于HPV-16。此外，虽然手术治疗对 宫颈的癌症和早期癌症病变，它与明显的发病率和高复发有关 阴道，外阴和肛门上皮内病变的发生率。因此，迫切需要发展创新 消除阴道，外阴和肛门中的持久性高危HPV感染，尤其是HPV-16的治疗方法。在 为了开发有效的HPV-16感染和HPV-16相关的肛门生殖器的有效治疗方法 病变，必须开发慢性HPV感染的临床前模型。现在很明显高风险HPV E6和E7致癌蛋白负责HPV相关病变的恶性进展。我们 最近产生了一个携带能够表达荧光素酶的DNA构建体的HPV-16伪旋转（PSV）（PSV） HPV E6和E7癌基因和RAS癌基因分别。我们发现被此HPV-16 PSV感染的小鼠 阴道感染后150天后，持续表达的荧光素酶以及E6和E7癌基因。在 比较，携带荧光素酶的HPV-16 PSV仅显示瞬时表达 编码基因。因此，我们创建了一个非侵入性成像系统，以遵循 e6/e7在阴道中。当前项目的目的是表征动物模型是否类似 持续的肛门生殖器HPV感染，并研究分子发病机理和免疫反应 持续的感染发展为癌变和癌症病变。我们的具体目的是：（1）表征 持续性HPV-16 E6/E7的分子发病机理和阴道，外阴和肛门的RAS表达 免疫能力和免疫功能低下的宿主以及（2）表征E6和E7特异性的体液和细胞 HPV-16 PSV持续性肛门生殖器感染后介导的免疫反应。成功 该项目的实现将生成持久性HPV-16 E6/E7表达式的临床前模型， 类似于慢性高风险HPV感染。这将代表一种可能改变的真正创新方法 HPV研究中的范式。此外，我们的临床前模型将促进分子的发展 针对E6/E7致癌蛋白控制HPV相关疾病的干预措施。结果 这项研究将对持续性HPV感染的管理和治疗具有重要意义。