Novel HIV-1 Microbicides

描述（由申请人提供）：异性传播占每年HIV-1感染新病例的大多数。世界卫生组织最近的报告估计，目前全世界共有3800万人感染HIV-1，其中90%生活在发展中国家。截至2003年，所有感染者中近50%是妇女。妇女、特别是育龄妇女感染艾滋病毒-1的发病率增加，突出表明迫切需要安全、负担得起和文化上可接受的有效预防和治疗办法。在缺乏有效的预防性疫苗的情况下，局部杀微生物剂可能提供一种实用的替代方案，以阻止HIV-1在进入部位的传播。我们寻求资金，以确定是否可以利用RNA干扰（RNAi）的过程来防止HIV-1的宫颈阴道传播，从而成为一种新的杀微生物策略。这项工作将由罗得岛医院（B）的研究者进行。Ramratnam）和Harvard-NEPRC（K.曼斯菲尔德）。RNAi是指在同源的短干扰（si）RNA的细胞引入之后的RNA的序列特异性降解。我们假设RNAi可以特异性靶向阴道/直肠粘膜，并降低介导HIV-1/SIV粘膜传播的宿主因子的表达。对于这些原理验证研究，我们将靶向猕猴中的CCR 5趋化因子受体。我们将在24个月内实现两个具体目标。1：表征直接阴道/直肠施用后脂质体siRNA的组织渗透率。2：定量在单次和连续阴道/直肠施用siRNA后粘膜CCR 5敲低的动力学和持久性。在12个月结束时，我们将确定siRNA的HIV-1杀微生物潜力。这一潜力的充分实现将来自更广泛的实验，包括在CCR 5 siRNA处理的猕猴和适当的对照中进行阴道/直肠病毒攻击。

DESCRIPTION (provided by applicant): 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. As of 2003, 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 cervicovaginal transmission of HIV-1 and thereby emerge as a novel microbicidal strategy. This work will be conducted by investigators at Rhode Island Hospital (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 vaginal/rectal mucosa 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 two specific aims over the 24-month period. 1: To characterize the tissue penetrance of liposomal siRNA following direct vaginal/rectal application. 2: To quantify the kinetics and durability of mucosal CCR5 knockdown following single and serial vaginal/rectal applications of siRNA. At the end of the 12-month period, we will have defined the HIV-1 microbicidal potential of siRNA. The full realization of this potential will come from more extended experiments involving vaginal/rectal virus challenge in CCR5 siRNA treated macaques and appropriate controls.