AAV Vectored Delivery of Broadly Neutralizing Antibodies with Optimal Innate Functionality Against HIV

项目总结/摘要 该提案描述了Alejandro Balazs博士的R 01赠款框架。巴拉兹博士是 目前是哈佛医学院的助理教授，担任Ragon的首席研究员 麻省理工学院和哈佛麻省总医院研究所。巴拉兹博士的研究重点是通过基因工程免疫系统 转移作为一种新的保护艾滋病毒的手段。广泛中和抗体（bNAb） 人类免疫缺陷病毒（HIV）在HIV预防和治疗中显示出巨大前景，因为它们有效地 中和全球广泛传播的艾滋病毒毒株。多项动物实验和临床 试验已经证明了bNAb能够提供保护免受病毒攻击并减少病毒血症。 建立感染。BNAb可以通过阻断病毒附着或膜融合来抑制HIV感染; 然而，最近的研究表明，抗体的可结晶片段（Fc）区也可能有助于 通过与先天免疫的相互作用，bNAb介导的HIV抑制作用显著。这项建议旨在 使用基于细胞的体外试验来确定下一代HIV bNAb与效应子 功能，如抗体依赖性细胞毒性（ADCC）和抗体依赖性细胞毒性（CD 34）。 吞噬作用（ADCP）。该提案将修改由Dr. Balazs产生先前携带精确Fc区突变的抗体的持续表达 证实增强或消除Fc-受体相互作用。通过操纵特异性， 这些抗体的浓度，本研究将定义适用于Fc受体结合的规则 预防艾滋病毒感染。此外，它试图确定Fc增强的抗体在免疫应答中的潜力。 增加bNAb保护HIV传播的效力。最后，这项建议将操纵 人源化小鼠的免疫系统作为解剖和精确定量 特异性免疫细胞预防艾滋病毒传播。总之，这项工作将揭示最佳表位靶点 和先天免疫机制，以产生编码具有增强的bNAb的下一代AAV载体。 先天免疫功能，以防止艾滋病毒的传播。

Project Summary / Abstract This proposal describes the framework of an R01 grant for Alejandro Balazs, PhD. Dr. Balazs is currently an assistant professor at Harvard Medical School working as a principal investigator at the Ragon Institute of MGH, MIT & Harvard. Dr. Balazs’ research is focused on engineering the immune system via gene transfer as a novel means of creating protection against HIV. Broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) show great promise in HIV prevention and therapy as they potently neutralize a significant breadth of globally circulating HIV strains. A number of animal experiments and clinical trials have demonstrated the ability of bNAbs to confer protection from viral challenge and reduce viremia of established infections. BNAbs can inhibit HIV infection by blocking viral attachment or membrane fusion; however, recent work suggests that the fragment crystallizable (Fc) region of antibodies may also contribute significantly to bNAb-mediated HIV inhibition through interactions with innate immunity. This proposal seeks to use in vitro cell-based assays to determine the extent to which next-generation HIV bNAbs engage effector functions, such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). This proposal will modify the Vectored ImmunoProphylaxis technology pioneered by Dr. Balazs to generate sustained expression of antibodies harboring precise Fc-region mutations previously demonstrated to enhance or abrogate, Fc-receptor interactions. By manipulating the specificity and concentration of these antibodies, this study will define the rules governing Fc-receptor engagement that apply to prevention of HIV acquisition. Furthermore, it seeks to determine the potential for Fc-enhanced antibodies to increase the potency of bNAb protection against HIV transmission. Finally, this proposal will manipulate the immune system of humanized mice as a means of dissecting and precisely quantifying the contribution of specific immune cells to prevention of HIV transmission. Together, this work will reveal optimal epitope targets and innate immune mechanisms to produce next-generation AAV vectors encoding bNAbs with enhanced innate immune function to prevent HIV transmission.