PAPILLOMAVIRUS MODEL SYSTEMS FOR MICROBICIDES

用于杀菌剂的乳头状病毒模型系统

• 批准号: 6201233
• 负责人: NEIL D CHRISTENSEN
• 金额: $ 5.82万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-29 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6201233
• 关键词: antiviral agents; athymic mouse; bovine papillomavirus; clinical research; disease /disorder model; drug screening /evaluation; enzyme linked immunosorbent assay; human papillomavirus; human tissue; laboratory rabbit; male reproductive system; microorganism disease chemotherapy; model design /development; monoclonal antibody; neutralizing antibody; polymerase chain reaction; rabbit papillomavirus; sexually transmitted diseases; tissue /cell culture; vagina; xenotransplantation

Human papillomaviruses (HPVs) represent some of the most common of the sexually transmitted disease. More than 80 HPV types have been identified and several types have been strongly implicated as causative agents in the onset of cervical vaginal, penile, oral and skin cancers. HPV DNA is present in virtually all cases (93 percent) of cervical cancer and its precursor lesions. Current microbicidal compounds with papillomavirus activity have not been described. In addition, there are not published reports of animal models of genital papillomavirus infections for testing intra-vaginal formulations and co-incidental STD infections. Recently, several in vitro and in vivo papillomavirus infectivity models have been documented that make feasible the screening and testing of microbicidal compounds and formulations for potential anti- papillomavirus activity. The purpose of this renewal proposal is to establish the validity of two in vitro and two in vivo papillomavirus infectivity models for the testing of microbicidal papillomavirus compounds. The in vitro models we propose to use are (I) BPV-1-induced focus formation of mouse C127 cells, and (ii) transient in vitro HPV-11 (and HPV-40) infection of human A431 epithelial cells using an ELISA-based RT-PCR detection of HPV E1 E4 spliced mRNA transcripts. We will use the in vitro models to screen for effective anti-papillomavirus compounds to be later tested in two animal model systems. These include a novel human vaginal xenograft animal model system using infectious HPV-11 and HPV-40 virions, and a rabbit genital papillomavirus model recently developed in our laboratory. During the first 3 years of this Program Project, we have identified several potential papillomavirus microbicidal compounds and have begun to characterize in vivo model of genital papillomavirus infections. These microbicidal agents (neutralizing monoclonal antibodies and alkyl sulfates) represent the first compounds with anti-papillomavirus activity. We will continue their characterizing and expand the testing using formulations delivered intra-vaginally (into human vaginal xenografts and into intact rabbit vaginas) for in vivo efficacy.

人乳头瘤病毒(HPV)是一些最常见的性传播疾病。目前已鉴定出80多种HPV类型，其中几种类型与宫颈阴道癌、阴茎癌、口腔癌和皮肤癌的发病密切相关。人乳头瘤病毒DNA几乎存在于所有宫颈癌及其前驱病变中(93%)。目前还没有描述具有乳头瘤病毒活性的杀微生物剂。此外，还没有关于生殖器乳头瘤病毒感染的动物模型用于测试阴道内配方和伴发的STD感染的报道。最近，几种体外和体内的乳头瘤病毒感染性模型被证明是可行的，使筛选和测试具有潜在抗乳头瘤病毒活性的杀微生物活性化合物和制剂成为可能。这一更新建议的目的是建立两个体外和两个体内乳头瘤病毒感染性模型的有效性，用于测试抗微生物素的乳头瘤病毒化合物。我们建议使用的体外模型是(I)BPV-1诱导小鼠C127细胞形成病灶，(Ii)体外瞬时感染HPV-11(和HPV-40)人A431上皮细胞，方法是基于EL ISA的RT-PCR检测HPV E1 E4剪接的mRNA转录。我们将使用体外模型来筛选有效的抗乳头瘤病毒化合物，稍后将在两个动物模型系统中进行测试。其中包括使用传染性HPV-11和HPV-40病毒粒子的新型人阴道异种移植动物模型系统，以及我们实验室最近开发的兔生殖器乳头瘤病毒模型。在该计划项目的前3年，我们已经确定了几种潜在的乳头瘤病毒杀微生物剂，并已开始表征生殖器乳头瘤病毒感染的体内模型。这些杀菌剂(中和单抗和烷基硫酸盐)代表了第一批具有抗乳头瘤病毒活性的化合物。我们将继续他们的特征，并扩大使用阴道内(进入人阴道异种移植物和进入完整的兔阴道)的配方进行体内有效性的测试。