Novel HIV-1 Microbicides

新型 HIV-1 杀菌剂

• 批准号: 7140588
• 负责人: Bharat Ramratnam
• 金额: $ 23.83万
• 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/7140588
• 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）：每年新的HIV-1感染病例中大多数的异性传播。世界卫生组织的最新报道估计，现在总共有3800万人感染了HIV-1。 90％的人居住在发展中国家。截至2003年，所有受感染的人中有近50％是女性。女性HIV-1感染的发病率增加，尤其是育龄年龄的人，强调了迫切需要安全，负担得起和文化接受的有效预防和治疗选择。在没有有效的预防性疫苗的情况下，局部菌皮可以为阻断进入现场的HIV-1传播提供一种实用的替代方法。我们寻求资金来确定是否可以利用RNA干扰过程（RNAI）来防止HIV-1的宫颈阴道传播，从而成为一种新型的杀生策略。这项工作将由罗德岛医院（B. Ramratnam）和哈佛NEPRC（K. Mansfield）的调查人员进行。 RNAi指的是RNA的序列特异性降解，该序列是遵循同源，短干扰（SI）RNA的细胞引入的。我们假设RNAi可以专门针对阴道/直肠粘膜，并降低介导HIV-1/SIV粘膜传播的宿主因子的表达。对于这些原则研究，我们将瞄准猕猴中的CCR5趋化因子受体。我们将在24个月期间追求两个具体目标。 1：表征直接阴道/直肠施用后脂质体siRNA的组织渗透性。 2：量化siRNA的单一阴道/直肠应用后，量化粘膜CCR5敲低的动力学和耐用性。在12个月结束时，我们将定义siRNA的HIV-1微生物潜能。该潜力的全部实现将来自更扩展的实验，这些实验涉及CCR5 siRNA处理过的猕猴和适当的对照中的阴道/直肠病毒挑战。