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3 500万人受到感染 在全球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）感染使控制和抑制感染成为可能， 世界各地目前没有得到这些药物，导致数百万可预防的死亡。那些有机会 HAART治疗仍有持续感染，需要终身坚持抗病毒治疗，以治疗病毒血症 抑制，并且存在不断出现的病毒耐药性的威胁。这需要继续 HIV-1新疗法研究。分离有效的广泛中和单克隆抗体 在被动转移后两个月内可以控制人类感染的抗体（bnAbs）显示， HIV-1感染者的新的潜在疗法。在这个建议中，我的目的是调查利用 “载体免疫预防”（VIP），其中腺相关病毒载体用于全身性递送 单克隆抗体，作为一种新型的HIV免疫治疗，有效地控制和抑制病毒 复制的该提案旨在模拟即将进行的人类临床试验， 并将检查预防免疫治疗所需的各种AAV载体bnAb的浓度。 人源化小鼠中受抑制的患者PBMC中的HIV-1病毒生长。此外，BLT人源化小鼠 将用于检测载体bnAb组合抑制复制HIV-1的能力， 独立于HAART治疗，此外，研究单克隆抗体治疗的影响 对人源化小鼠免疫应答功能的影响。最终，该提案将预测 即将进行的临床试验的成功和利用持续的单克隆抗体表达系统的功效 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.