Novel HIV-1 Microbicides

新型 HIV-1 杀菌剂

• 批准号: 7006803
• 负责人: Bharat Ramratnam
• 金额: $ 21.88万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7006803
• 关键词: AIDS education /prevention; HIV infections; Macaca; RNA interference; antiAIDS agent; biotechnology; cell surface receptors; chemokine receptor; confocal scanning microscopy; cytokine; drug screening /evaluation; enzyme linked immunosorbent assay; fluorescent dye /probe; host organism interaction; human immunodeficiency virus 1; liposomes; microorganism disease chemotherapy; mucosal immunity; nonhuman therapy evaluation; rectum /anus; small interfering RNA; therapy design /development; vagina; virus infection mechanism

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.

描述（由申请人提供）：每年新发 HIV-1 感染病例的大部分是异性传播。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% 是女性。女性（尤其是育龄女性）HIV-1 感染发病率的增加凸显了迫切需要安全、负担得起且文化上可接受的有效预防和治疗方案。在缺乏有效的预防性疫苗的情况下，外用杀菌剂可能提供一种实用的替代方案来阻止 HIV-1 在入境地点传播。我们寻求资金来确定是否可以利用 RNA 干扰 (RNAi) 过程来预防 HIV-1 的宫颈阴道传播，从而成为一种新型的杀菌策略。这项工作将由罗德岛医院 (B. Ramratnam) 和哈佛大学 NEPRC (K. Mansfield) 的研究人员进行。 RNAi 是指在细胞中引入同源短干扰 (si) RNA 后发生的 RNA 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，并减少介导 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，我们将针对猕猴中的 CCR5 趋化因子受体。我们将在 24 个月内实现两个具体目标。图 1：表征直接阴道/直肠施用后脂质体 siRNA 的组织渗透性。图 2：量化单次和连续阴道/直肠应用 siRNA 后粘膜 CCR5 敲低的动力学和持久性。 12 个月结束时，我们将确定 siRNA 的 HIV-1 杀菌潜力。这种潜力的充分实现将来自于更广泛的实验，包括在 CCR5 siRNA 处理的猕猴和适当的对照中进行阴道/直肠病毒攻击。