Novel Si RNA microbicides to prevent HIV-1 infectio

每年新增的HIV-1感染病例中，异性传播占大多数。近期 来自世界卫生组织的报告估计，目前共有3800万人感染了艾滋病 全球艾滋病毒-1；其中90%生活在发展中国家。近50%的感染者是 女人。艾滋病毒-1感染在妇女中的发病率增加，特别是育龄妇女， 强调迫切需要安全、负担得起和有效的预防和治疗办法 在文化上被接受。在缺乏有效的预防性疫苗的情况下，局部使用的杀微生物剂可能会提供 在入口处阻断艾滋病毒-1传播的实用替代方案。我们寻求资金以确定是否 可以利用RNA干扰(RNAi)过程来防止艾滋病毒-1的宫颈-阴道传播 并因此成为一种新的杀微生物剂策略。这项工作将由罗德的调查人员进行 岛医院，布朗大学(B.Ramratnam)和哈佛-NEPRC(K.Mansfield)。RNAi指的是 RNA在细胞中引入同源短干扰后的序列特异性降解 (Si)RNA。我们假设RNAi可以特异性地靶向粘膜表面，并减少 介导HIV-1/SIV粘膜传播的宿主因子的表达。对于这些原则证明研究， 我们将针对猕猴的CCR5趋化因子受体。我们将在12年内实现三个具体目标- 一个月的期间。1：脂质体和纳米囊剂siRNA的组织渗透性研究 在直接粘膜涂抹后。2：量化黏膜CCR5基因敲除的动力学和持久性 在单次和连续的小干扰RNA粘膜应用之后。3.开展病毒挑战实验 小干扰RNA处理的动物。在授权期结束时，我们将确定艾滋病毒-1杀微生物剂 SiRNA的潜力。

Heterosexual transmission accounts for the majority of new cases of HIV-1 infection each year. Recent reports from the World Health Organization estimate that a total of 38 million people are now infected with HIV-1 worldwide; 90% of whom live in developing countries. Nearly 50% of all infected individuals were women. The increased incidence of HIV-1 infection in women, particularly those of childbearing age, underscores the urgent need for effective preventative and therapeutic options that are safe, affordable and culturally accepted. In the absence of an effective preventative vaccine, topical microbicides may offer a practical alternative to block HIV-1 transmission at the site of entry. We seek funds to determine whether the process of RNA interference (RNAi) can be harnessed to prevent the cervico-vaginal transmission of HIV-1 and thereby emerge as a novel microbicidal strategy. This work will be conducted by investigators at Rhode Island Hospital, Brown University (B. Ramratnam) and Harvard-NEPRC (K. Mansfield). RNAi refers to the sequence-specific degradation of RNA that follows the cellular introduction of homologous, short interfering (si) RNA. We hypothesize that RNAi can be specifically targeted to the mucosal surfaces and decrease the expression of host factors that mediate HIV-1/SIV mucosal transmission. For these proof-of-principle studies, we will target the CCR5 chemokine receptor in macaques. We will pursue three specific aims over the 12- month period. 1: To characterize the tissue penetrance of liposomal and nanaocapsule formulated siRNA following direct mucosal application. 2: To quantify the kinetics and durability of mucosal CCR5 knockdown following single and serial mucosal applications of siRNA. 3. To conduct virus challenge experiments in siRNA treated animals. At the end of the granting period, we will have defined the HIV-1 microbicidal potential of siRNA.