Cyclodextrin as a Novel HIV Microbicide

描述（由申请人提供）： 事实证明，当地使用的生物医学屏障和杀微生物剂对预防艾滋病毒的性传播无效。HIV需要完整的脂筏，细胞膜中富含胆固醇的亚区，以进入细胞和感染性颗粒的出芽。β-环糊精（？- CD），一种从细胞膜上除去胆固醇并分散脂筏的环状七糖，已被证明可以阻断HIV感染并消除萌芽HIV颗粒的感染性。胆固醇也需要其他病原体，包括许多病毒，其中一些与性病有关，如HSV-2。??- CD是无毒的，广泛用于食品和药物载体中。许多对人类和动物的研究表明，CD可以安全地应用于粘膜表面。因此，适当配制，这种分子可能是一种安全的杀微生物剂，对艾滋病毒和其他病原体有效。这一建议的中心假设是，由于它有效地消耗脂膜中的胆固醇，从而阻断病毒感染，并在人体中具有广泛和公认的安全性，CD是用作局部阴道HIV杀微生物剂的杰出候选者。在这个项目的头两年里，我们已经证明了？CD在细胞和病毒水平阻断HIV感染，并确定了化合物灭活病毒体的机制。我们还展示了？- CD在Hu-SCID小鼠模型中有效阻断了阴道HIV传播。我们的研究已经确定了最有效的艾滋病毒杀微生物剂的三个基本标准：消灭每一个病毒颗粒;不破坏感染的天然屏障;不诱导炎症反应。在继续这个项目，我们将继续专注于机制，同时优化参数的使用？CD作为HIV杀微生物剂。具体目标是：1.为了确定制剂的效果，CD的抗HIV-1活性; 2.为了确定？？- CD对小鼠和恒河猴模型阴道上皮细胞的体外和体内作用; 3.以确定是否有害影响？-细胞膜上的CD可以被外源脂质所减弱; 4.决定？- CD与其他药物在阻断HIV感染方面具有协同作用。这些研究应该提供关于HIV杀微生物剂总体发展的重要见解，尤其是CD。这些结果将为进一步的动物研究和这种新型杀微生物剂候选物的初步人体研究提供基础。

DESCRIPTION (provided by applicant): Locally applied biomedical barriers and microbicides have proven ineffectual in preventing sexual transmission of HIV. HIV requires intact lipid rafts, cholesterol-rich subregions in cell membranes, for entry into cells and for budding of infectious particles. Beta-cyclodextrin (?-CD), a cyclic heptasaccharide that removes cholesterol from cell membranes and disperses lipid rafts, has been shown to block HIV infection and abolish infectivity of budding HIV particles. Cholesterol is also required by other pathogens including many viruses, some of which are associated with STDs such as HSV-2. ??-CD is non-toxic and in wide human use in food products and as a carrier for drugs. A number of studies in humans and animals have shown that ?-CD can be safely applied to mucosal surfaces. Thus properly formulated, this molecule may be a safe microbicide effective against HIV and other pathogens. The central hypothesis of this proposal is that because it efficiently depletes cholesterol from lipid membranes thereby blocking virus infection and has an extensive and well-established safety profile in humans, ?-CD is an outstanding candidate for use as topical vaginal HIV microbicide. Over the first two years of this project we have shown that ?-CD blocks HIV infection at the level of cells and virus and defined mechanisms by which the compound inactivates virions. We also showed that ?-CD effectively blocked vaginal HIV transmission in a Hu-SCID mouse model. Our studies have identified three criteria essential for the most effective HIV microbicide: inactivate every virus particle; do not disrupt the natural barriers to infection; and do not induce an inflammatory response. In continuing this project we will remain focused on mechanisms while optimizing parameters for use of ?-CD as an HIV microbicide. The specific aims are: 1. To determine the effects of formulation of??-CD on its anti-HIV-1 activity; 2. To determine the effect of??-CD on vaginal epithelium in vitro and in vivo in mouse and rhesus macaque models; 3. To determine if deleterious effects of ?-CD on cell membranes can be attenuated by exogenous lipid; 4. To determine ?-CD is synergistic with other agents In blocking HIV infection. These studies should provide important insights regarding the development of HIV microbicides generally and ?-CD in particular. The results should provide the basis for further animal studies and pilot human studies of this novel microbicide candidate.