Aptamer Microbicide Development Program (MDP)

描述（由申请人提供）：在缺乏艾滋病毒疫苗且避孕套使用不一致的情况下，艾滋病流行继续加剧。性接触是主要的感染途径，女性受到的影响尤其严重。在这种情况下，迫切需要开发新的女性控制预防技术，包括杀微生物剂。理想情况下，杀菌剂应能预防 HIV-1 和其他常见性传播感染 (STI)，例如单纯疱疹病毒 (HSV) 和人乳头瘤病毒 (HPV)。这些产品应该安全、有效、可接受且制造成本低廉。它们还应该能够用于阴道和直肠室。这笔资助的目的是利用适体技术来产生具有抗 HIV-1、HSV-2 和 HPV-16 活性的候选杀微生物剂。选择 HSV-2 和 HPV-16 是因为已知它们会增加 HIV-1 传播 (HSV-2) 的风险或与宫颈癌和肛门癌 (HPV-16) 的发展有关。适体是通过体外进化过程从大规模复杂的组合文库衍生的核酸配体，通常称为指数富集配体系统进化（SELEX）。适体能够以高亲和力与重要的蛋白质靶标结合，并产生包括降低病毒感染性在内的生物学后果。在本提案中，我们将测试以下假设：(1) 可以开发单独的抗病毒适体，通过体外细胞攻击实验证明对 HIV-1、HSV-2 和 HPV-16 的功效，(2) 可以在子宫颈阴道、肠道和肛门组织外植体系统中证明抗病毒功效，并且当适体作为单一药物或组合给予时不会改变，以及 (3) 抗病毒适体的组合可以当在攻击实验中使用多种病毒时，防止外植体系统感染。该研究将由牛津大学（适体发现）、RNA-Tec（适体优化和放大）和加州大学洛杉矶分校（组织外植体研究）的联盟进行。

DESCRIPTION (provided by applicant): In the absence of a HIV vaccine, and with inconsistent use of condoms, the AIDS pandemic continues to gather momentum. Sexual exposure is the primary route of infection with women becoming disproportionately affected. In this setting, there is an urgent need to develop new female controlled prevention technologies including microbicides. Ideally, microbicides should provide protection against HIV-1 and other common sexually transmitted infections (STIs) such as herpes simplex virus (HSV) and human papilloma virus (HPV). These products should be safe, effective, acceptable and cheap to manufacture. They should also be able to be used in both the vaginal and rectal compartments. The purpose of this grant is to use aptamer technology to generate individual candidate microbicides with activity against HIV-1, HSV-2 and HPV-16. HSV-2 and HPV-16 have been chosen because they are known to increase the risk of HIV-1 transmission (HSV-2) or are linked to the development of cervical and anal cancer (HPV-16). Aptamers are nucleic acid ligands derived from massively complex combinatorial libraries by a process of in vitro evolution, often referred to as systematic evolution of ligands by exponential enrichment (SELEX). Aptamers have the capacity to bind to important protein targets with high affinity and biological consequences including reducing viral infectivity. In this proposal we will test the following hypotheses: (1) Individual antiviral aptamers can be developed that demonstrate efficacy against HIV-1, HSV-2, and HPV-16 using in-vitro cell challenge experiments, (2) Antiviral efficacy can be demonstrated in cervico-vaginal, intestinal, and anal tissue explant systems and is not altered when aptamers are given as single agents or in combination, and (3) Combinations of antiviral aptamers can prevent infection of explant systems when multiple viruses are used in challenge experiments. The study will be undertaken by a consortium based at Oxford University (aptamer discovery), RNA-Tec (aptamer optimization and scale-up) and UCLA (tissue explant studies).