Cyclodextrin as a Novel HIV Microbicide

描述(由申请人提供)： 当地应用的生物医学屏障和杀微生物剂已被证明在预防艾滋病毒的性传播方面无效。HIV需要完整的脂筏，细胞膜中的富含胆固醇的亚区，才能进入细胞和发芽感染颗粒。β-环糊精(？-CD)是一种环状七糖，可以去除细胞膜上的胆固醇，分散脂筏，已被证明可以阻断HIV感染，并消除萌芽中的HIV颗粒的传染性。其他病原体也需要胆固醇，包括许多病毒，其中一些与性病有关，如HSV-2。？？-镉无毒，在人类食品中广泛使用，也是药物的载体。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，如果配方得当，该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。这项建议的中心假设是，因为它有效地从脂膜中耗尽胆固醇，从而阻止病毒感染，并且在人类中具有广泛和良好的安全性，？-CD是作为局部阴道艾滋病毒杀菌剂的杰出候选药物。在这个项目的头两年里，我们已经证明了？-CD在细胞和病毒水平上阻止艾滋病毒感染，并确定了该化合物灭活病毒粒子的机制。在HU-SCID小鼠模型中，我们还显示了？-CD有效地阻断了艾滋病毒的阴道传播。我们的研究确定了最有效的艾滋病毒杀微生物剂的三个基本标准：使每个病毒颗粒灭活；不破坏感染的自然屏障；不引发炎症反应。在继续这个项目中，我们将继续关注机制，同时优化使用β-环糊精作为艾滋病毒杀菌剂的参数。其具体目的是：1.确定β-CD制剂对其抗HIV-1活性的影响；2.测定β-CD在体外和体内对小鼠和恒河猴阴道上皮细胞的影响；3.确定外源性脂质能否减弱？-CD对细胞膜的有害作用；4.确定？-CD与其他药物在阻断HIV感染方面是否具有协同作用。这些研究应该对艾滋病毒杀微生物剂的发展，特别是-CD的发展提供重要的见解。这些结果应该为进一步的动物研究和这种新型杀菌剂候选的人体试验提供基础。

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.