Development of Vectored ImmunoProphylaxis as a strategy against HIV

描述(由申请人提供)：本提案描述了为Alejandro B.Balazs博士提供的过渡性赠款的框架。这笔赠款将在巴拉兹博士获得助理教授职位后启动，并将为最初几年的工作提供资金。巴拉兹博士目前是加州理工学院大卫·巴尔的摩实验室的博士后学者。巴拉兹博士的研究重点是通过基因转移来设计免疫系统，作为一种新的方法，在被称为载体免疫预防(VIP)的过程中创建对传染病的保护。这项提议的重点是扩大最近通过VIP提供的单抗在人源化小鼠中预防艾滋病毒感染的演示。该提案旨在通过确定最近描述的几种广泛中和抗体的体内效力来扩大这些发现，这些抗体在体外表现出比之前描述的更大的中和效力和广度。它将研究VIP预防传播的艾滋病毒创始人毒株感染的潜力。它还旨在建立人与人之间传播的模型，并在第二个表现出更强免疫功能的人源化小鼠模型中确定VIP对艾滋病毒感染的保护程度。最后，它将检查逃逸突变对低浓度中和抗体表达时VIP失败的贡献。总之，这项工作将扩大我们对使用基因转移提供的中和抗体作为预防艾滋病毒的潜力的理解，并将探索病毒逃逸，这可能会破坏这种和其他疫苗方法在人类身上的有效性。

DESCRIPTION (provided by applicant): This proposal describes the framework of a transitional grant for Alejandro B. Balazs, PhD. The grant would be activated after Dr. Balazs obtains an assistant professor position and would provide funding for the initial years of work. Dr. Balazs is currently a postdoctoral scholar in David Baltimore's laboratory at the California Institute of Technology. Dr. Balazs' research is focused on engineering the immune system via gene transfer as a novel means of creating protection against infectious disease in a process termed Vectored ImmunoProphylaxis (VIP). This proposal is focused on extending the recent demonstration of protection against HIV infection in humanized mice by monoclonal antibodies delivered by VIP. The proposal aims to extend these findings by determining the in vivo potency of several recently described broadly neutralizing antibodies that, in vitro, exhibited greater potency and breadth of neutralization than those described previously. It will study the potential for VIP to prevent infection by transmitted founder strains of HIV. It also aims to model human-to-human transmissions and determine the degree of protection against HIV infection conferred by VIP in a second humanized mouse model that exhibits greater immunological function. Finally, it will examine the contribution of escape mutations to the failure of VIP when expressing low concentrations of neutralizing antibodies. Together, this work will expand our understanding of the potential of using neutralizing antibodies delivered by gene transfer as prophylaxis against HIV, and it will explore viral escape, which might undermine the effectiveness of this and other vaccine approaches in humans.