Aptamer Microbicide Development Program (MDP)

描述（由申请人提供）：在没有艾滋病毒疫苗的情况下，以及不一致地使用避孕套，艾滋病流行继续聚集势头。性接触是感染的主要途径，妇女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的预防技术，包括杀微生物剂。理想情况下，杀微生物剂应提供对HIV-1和其他常见性传播感染（STI）的保护，如单纯疱疹病毒（HSV）和人乳头瘤病毒（HPV）。这些产品应该是安全、有效、可接受和廉价的。它们也应该能够用于阴道和直肠隔室。这项资助的目的是利用适体技术生产具有抗HIV-1、HSV-2和HPV-16活性的单个候选杀微生物剂。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组合文库衍生的核酸配体，所述体外进化过程通常被称为指数富集配体系统进化（SELEX）。适体具有以高亲和力和生物学后果（包括降低病毒感染性）结合重要蛋白质靶标的能力。在本提案中，我们将检验以下假设：（1）可以开发单独的抗病毒适体，其使用体外细胞攻击实验证明抗HIV-1、HSV-2和HPV-16的功效，（2）抗病毒功效可以在宫颈-阴道、肠和肛门组织外植体系统中证明，并且当适体作为单一药剂或组合给予时不改变，和（3）当在攻击实验中使用多种病毒时，抗病毒适体的组合可以防止外植体系统的感染。该研究将由牛津大学（适体发现），RNA-Tec（适体优化和规模化）和UCLA（组织外植体研究）的财团进行。

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).