A topical treatment for genital papillomavirus infections

描述(由申请人提供)：与年龄调整的人群相比，艾滋病毒阳性个人的HPV感染及其肿瘤前后遗症的患病率更高。虽然预防性疫苗将很快上市，用于预防HPV感染和宫颈癌，但这些疫苗对已经感染HPV的艾滋病毒阳性妇女几乎没有好处。此外，这些疫苗无法预防感染几种HPV类型，这些类型占宫颈癌的20%-30%。迫切需要治疗和预防策略来对抗这些HPV损害。在这项申请中，我们将检查两种化合物，它们在预防和治疗这种性传播疾病方面显示出巨大的潜力。第一个化合物是卡拉胶，约翰·席勒博士的实验室最近证明，它通过阻断细胞附着，在体外对乳头瘤病毒感染起到了有效的抑制作用。这是一种用于食品制剂的无毒化合物，我们将与席勒博士协商，评估卡拉胶抑制阴道乳头瘤病毒感染的能力。第二个化合物是双氢青蒿素(从中草药青蒿素中提取)。双氢青蒿素强烈诱导表达HPV的宫颈细胞的凋亡，并防止体内肿瘤的形成(使用犬口腔乳头状瘤病毒模型)。在这项应用中，我们建议建立第一个体内检测女性生殖道乳头瘤病毒感染的方法。我们的头两年(R21阶段)将专注于适应犬口腔乳头瘤病毒(COPV)，这种病毒通常会感染口腔粘膜，并在阴道粘膜中诱导肿瘤。在人类中，口腔和生殖器粘膜感染的是相同类型的HPV。在狗身上，COPV偏爱口腔粘膜，但如果动物受到轻微的免疫抑制，它也可能传播到生殖道。我们计划使用记录在案的免疫抑制方法来开发一种简单且可重复性的检测阴道上皮乳头瘤病毒感染的方法。在应用的R33阶段，我们将研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。这一新的动物模型与新发现的乳头状瘤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。

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.