Immunoglobulins Delivered by AAV Vector for the Prevention of SIV Infection

描述(申请人提供)：AAV载体最近被用来传递单链抗体免疫粘附素(ScFVI)版本的恒河猴抗体，具有中和SIV的活性。在9只恒河猴中，有6只获得了持续高水平的scFVI，这6只猕猴对SIV攻击表现出了杀菌屏障。九只猴子中有三只对它们收到的scFVI产生了抗体反应，这三只没有受到SIV攻击的保护。 将对两种不同的方法进行比较，以实现AAV载体递送这些ScFVI的真实免疫球蛋白版本。我们将确定交付真正的免疫球蛋白是否会降低观察到抗-抗反应的频率。我们将确定AAV载体是否可以用来运送二聚体分泌型IgA，以及分泌型IgA是否通过粘膜途径提供了更有效的屏障来对抗SIV感染。最后，我们将确定抗体依赖的细胞毒性对4L6和5L7的免疫球蛋白的保护作用是否重要。在恒河猴身上进行的这些实验结果将为人类预防HIV-1感染的类似载体的开发提供信息和指导。 与公共卫生相关：尚未制定成功的策略来激发具有强大的广谱中和活性的抗体来对抗HIV-1野生型毒株。利用AAV载体传递具有强大的广谱中和活性的预定义抗体是创建HIV-1感染的灭菌屏障的一种新的有前途的策略。建议的结果 在恒河猴身上进行的实验将为这种媒介的发展提供信息和指导，以防止人类感染艾滋病毒-1。

DESCRIPTION (provided by applicant): AAV vector has recently been used to deliver single chain Fv immunoadhesin (scFVI) versions of rhesus monkey antibodies with neutralizing activity against SIV. High, persisting levels of scFVI were achieved in 6 of 9 rhesus monkeys and these six exhibited a sterilizing barrier against SIV challenge. Three of the nine monkeys developed antibody responses to the scFVI that they received and these three were not protected against SIV challenge. Two different approaches will be compared for AAV vector delivery of the authentic IgG version of these scFVIs. We will determine whether delivery of authentic IgG decreases the frequency with which anti-anti responses are observed. We will determine whether AAV vector can be used to deliver dimeric secretory IgA and whether secretory IgA provides a more effective barrier to SIV infection by the mucosal route. Finally, we will determine whether antibody-dependent cellular cytotoxicity is important for the protective effects of the IgG versions of 4L6 and 5L7. Results from these experiments in rhesus monkeys will inform and guide development of analogous vectors for the prevention of HIV-1 infection in humans. PUBLIC HEALTH RELEVANCE: Successful strategies have not been devised for the elicitation of antibodies with potent broadly-neutralizing activity against field strains of HIV-1. Use of AAV vector to deliver predefined antibodies with potent, broadly-neutralizing activity is a novel promising strategy for creating a sterilizing barrier to HIV-1 infection. Results from the proposed experiments in rhesus monkeys will inform and guide development of such vectors for the prevention of HIV-1 infection in humans.