Immunoglobulins Delivered by AVV Vector for the Prevention of SIV Infection

项目摘要/摘要 在针对病毒疾病的经典免疫方法中，病毒蛋白被传递或 在疫苗接受者体内表达，希望由此产生的免疫反应是保护性的。为. 由于各种原因，这种经典的方法面临着成功抗击艾滋病毒-1的严重障碍。悲观主义者 实验室一直在研究一种非经典的方法，通过这种方法，一种病毒载体，腺相关病毒 (AAV)，用于实现抗HIV单抗(MAbs)的非常长期的递送，具有强大的 对广泛的HIV-1分离株具有中和活性。AAV载体已被证明在人类身上是安全的 目前是纠正遗传性酶/代谢缺陷的首选载体。 当转基因在肌肉内传递时，转基因表达可以持续数年、数十年，甚至终身，就像 只要转基因产品不被视为外来产品。我们的愿景是单次接种AAV载体 制造一种有效的广谱中和抗体的鸡尾酒将为其余的 个人的生命。尽管抗体可能被视为一种“自身”蛋白质，但对猴子的研究表明， 宿主抗体可能对递送的单抗产生反应，这可能严重限制单抗的浓度 这是可以实现的。Desrosiers实验室将继续朝着最大限度地减少反 问题，并使用恒河猴模型实现所需抗体的一致传递。这些研究 其直接目标是促进这一概念的发展，供人类使用。

Project Summary/Abstract In the classical approach to immunization against viral diseases, viral proteins are delivered or expressed in the vaccine recipient and it is hoped that the resultant immune responses are protective. For a variety of reasons, such a classic approach faces severe obstacles to success against HIV-1. The Desrosiers laboratory has been investigating a nonclassical approach by which a viral vector, adeno-associated virus (AAV), is used to achieve very long-term delivery of anti-HIV monoclonal antibodies (mAbs) with potent neutralizing activity against a broad spectrum of HIV-1 isolates. AAV vectors have proven safe in human testing and are currently the vector of choice for correction of hereditary enzyme/metabolism deficiencies. When delivered intramuscularly, transgene expression can continue for years, decades, probably for life, as long as the transgene product is not viewed as foreign. The vision is that a single inoculation of AAV vector making a cocktail of potent broadly-neutralizing antibodies will provide sterilizing immunity for the rest of the individual's life. Although an antibody may be viewed as a “self” protein, studies in monkeys have revealed that a host antibody response may occur to the delivered mAb and this may severely limit the concentration of mAb that can be achieved. The Desrosiers laboratory will continue its progress toward minimizing the anti-anti problem and achieving consistent delivery of desirable antibodies using rhesus monkey models. These studies are directly targeted to facilitating development of this concept for use in humans.