A topical treatment for genital papillomavirus infections

生殖器乳头瘤病毒感染的局部治疗

• 批准号: 7174571
• 负责人: Richard Schlegel
• 金额: $ 22.23万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7174571
• 关键词: Papillomavirus; dogs; infection; model; neoplasm /cancer

DESCRIPTION (provided by applicant): HIV-positive individuals have a higher prevalence of HPV infection and its pre-neoplastic sequelae than age-adjusted populations. While prophylactic vaccines will soon be available commercially for the prevention of HPV infection and cervical cancer, these vaccines will have little or no benefit for HIV-positive women who are already HPV-infected. In addition, theses vaccines do not prevent infection with several HPV types that account for 20-30% of cervical cancers. Therapeutic and preventative strategies to combat these HPV lesions are desperately needed. In this application, we will examine two compounds which show dramatic potential for preventing and treating this sexually transmitted disease. The first compound is carrageenan, which was recently shown by Dr. John Schiller's laboratory to be a potent inhibitor of papillomavirus infection in vitro by blocking cellular attachment. This is a non-toxic compound used in food preparations and, in consultation with Dr. Schiller, we will evaluate carrageenan's ability to inhibit vaginal papillomavirus infections. The second compound is dihydroartemisinin (derived from the Chinese herb, Artemisia annua). Dihydroartemisinin strongly induces apoptosis in HPV-expressing cervical cells and prevents tumor formation in vivo (using a canine oral papillomavirus model). In this application we propose to develop the first in vivo assay for papillomavirus infection of the female genital tract. Our first two years (the R21 phase) will focus on adapting the canine oral papillomavirus (COPV), which normally infects the oral mucosa, to infect and induce tumors in vaginal mucosa. In humans, the oral and genital mucosae are infected by the same HPV types. In the dog, COPV prefers the oral mucosa but it can also spread to the genital tract if the animals are mildly immunosuppressed. We plan to use documented methods of immunosuppression to develop a simple and reproducible assay for papillomavirus infection of vaginal epithelium. In the R33 phase of the application, we will formulate dihydroartemisinin derivatives and carrageenan and test them for their ability to inhibit papillomavirus infection, replication and tumor formation. We will also determine if viral persistence and latency are altered by these compounds. The combined use of this new animal model along with the newly identified inhibitors of papillomvirus infection offer exciting possibilities for extending these trials into humans.

描述（由申请人提供）：与年龄调整人群相比，HIV 阳性个体的 HPV 感染及其肿瘤前后遗症的患病率更高。虽然用于预防 HPV 感染和宫颈癌的预防性疫苗很快就会上市，但这些疫苗对于已经感染 HPV 的 HIV 阳性女性几乎没有或根本没有益处。此外，这些疫苗不能预防几种 HPV 类型的感染，这些类型的 HPV 占宫颈癌的 20-30%。迫切需要对抗这些 HPV 病变的治疗和预防策略。在此应用中，我们将研究两种在预防和治疗这种性传播疾病方面显示出巨大潜力的化合物。第一种化合物是角叉菜胶，约翰·席勒博士的实验室最近证明它通过阻断细胞附着而成为体外乳头瘤病毒感染的有效抑制剂。这是一种用于食品制剂的无毒化合物，在与席勒博士协商后，我们将评估角叉菜胶抑制阴道乳头瘤病毒感染的能力。第二种化合物是二氢青蒿素（源自中草药青蒿）。双氢青蒿素强烈诱导表达 HPV 的宫颈细胞凋亡，并防止体内肿瘤形成（使用犬口腔乳头瘤病毒模型）。在本申请中，我们建议开发第一个针对女性生殖道乳头瘤病毒感染的体内测定法。我们的前两年（R21 阶段）将重点关注使通常感染口腔粘膜的犬口腔乳头瘤病毒（COPV）感染并诱发阴道粘膜肿瘤。在人类中，口腔和生殖器粘膜受到相同 HPV 类型的感染。在狗身上，COPV 更喜欢口腔粘膜，但如果动物轻度免疫抑制，它也可以传播到生殖道。我们计划使用已记录的免疫抑制方法来开发一种简单且可重复的阴道上皮乳头瘤病毒感染检测方法。在R33阶段的申请中，我们将配制双氢青蒿素衍生物和卡拉胶，并测试它们抑制乳头瘤病毒感染、复制和肿瘤形成的能力。我们还将确定这些化合物是否会改变病毒的持久性和潜伏期。这种新的动物模型与新发现的乳头状病毒感染抑制剂的结合使用为将这些试验扩展到人类提供了令人兴奋的可能性。