The Use of Monoclonal Antibodies Delivered by Viral Vector as an HIV-1 Therapeutic

项目摘要 尽管几十年来一直在努力减少艾滋病毒的传播，但目前仍有3500万人受到感染 全球范围内。虽然针对人类免疫缺陷的高效抗逆转录病毒疗法(HAART)的出现 1型病毒(HIV-1)感染使感染得以控制和抑制，很大一部分人 全世界目前没有接受这些药物，导致数百万可预防的死亡。那些有权访问的人 HAART治疗仍有持续性感染，需要终生坚持抗病毒治疗 而且存在不断出现的病毒耐药性的威胁。这就需要继续 抗HIV-1新疗法的研究。高效广谱中和单抗的分离 被动转移后两个月可以控制人类感染的抗体(BNAbs)揭示了一种 针对HIV-1感染者的新的潜在疗法。在这项提案中，我的目的是调查 ‘载体免疫预防’(VIP)，通过使用腺相关病毒载体来传递系统 体内单抗作为一种有效控制和抑制病毒的新型HIV免疫疗法 复制。这项提议旨在模仿即将进行的人类临床试验，测试矢量化的bNAbs 免疫疗法，并将检测各种AAV载体bNAb的浓度，以防止 HIV-1病毒在人源化小鼠中抑制患者PBMC中的生长。此外，BLT人源化小鼠 将用于检测矢量化bNAb组合抑制HIV-1复制的能力， 独立于HAART治疗，并进一步研究单抗治疗的影响 关于人源化小鼠免疫反应的功能。最终，这项提案将预测 即将进行的临床试验的成功和利用持续的单抗表达系统的有效性 作为HAART的替代疗法。

Project Summary Despite decades of effort to reduce HIV transmission, 35 million individuals are still presently infected globally. While the advent of highly active antiretroviral therapy (HAART) against human immunodeficiency virus type 1 (HIV-1) infection has enabled the control and suppression of infection, a large fraction of people worldwide do not currently receive these drugs, resulting in millions of preventable deaths. Those with access to HAART treatment still have persistent infection requiring lifelong adherence to antiviral therapy for viremic suppression and there exists the constant threat of emerging viral resistance. This necessitates continuing investigation into new therapeutics against HIV-1. Isolation of potent broadly neutralizing monoclonal antibodies (bnAbs) that can control infection in humans up to two months after passive transfer has revealed a new potential therapy for HIV-1 infected individuals. In this proposal, I aim to investigate the utilization of `vectored immunoprophylaxis' (VIP), whereby an adeno-associated virus vector is used to deliver systemic monoclonal antibody in vivo, as a novel HIV immunotherapy to effectively control and suppress viral replication. This proposal aims to mimic impending human clinical trials testing vectored bnAbs as immunotherapeutics and will examine the concentration of various AAV-vectored bnAbs required to prevent HIV-1 viral outgrowth in suppressed patient PBMC's in humanized mice. Additionally, BLT humanized mice will be used to examine the ability of combinations of vectored bnAbs to suppress replicating HIV-1, independent of HAART therapy and furthermore, investigate the impact that monoclonal antibody therapy has on the functionality of the immune response in humanized mice. Ultimately, this proposal will predict the success of upcoming clinical trials and efficacy of utilizing a sustained monoclonal antibody expression system as an alternative therapy to HAART.