Biomaterials-Enhanced NK Cells for Improved Elimination of the HIV Reservoir

项目摘要 高效抗逆转录病毒疗法降低了艾滋病毒/艾滋病的发病率和死亡率，但并没有导致艾滋病毒/艾滋病的死亡。 疗方即使在治疗良好的个体中，病毒在潜伏宿主中的持续存在也会导致终身感染。 对这些药物的承诺。因此，患者仍然承受着合并症的负担， 暴露在艾滋病毒阳性带来的负面社会问题中。因此，迫切需要 开发能够从个体中根除病毒的治疗策略， 改善艾滋病毒/艾滋病感染者的生活。针对这一需要，我们建议将以下行动联合收割机 潜伏期逆转剂（LRA）、广泛中和抗体（bnAb）和活化的自然杀伤细胞（NK） 在一个单一的治疗平台内。更具体地说，我们建议使用生物工程策略， 设计一种整体生物杂交治疗药物，其中LRA和bnAb包装在聚（乳酸-乙醇酸共聚物）中 酸）（PLGA）纳米颗粒库（纳米库），然后附着在NK细胞的表面上。我们预计 LRA与NK细胞活化和局部bnAb存在的共定位将引发更有效的免疫应答。 并协调根除持续存在的艾滋病毒储存库。在本项目的R21阶段，我们建议 工程NK纳米库封装LRA和bnAb，作为保留表型的现成生物杂合物 以及NK细胞和包封的LRA和bnAb的功能。一个函数的实现 成功协调LRA、bnAb和NK细胞作用的整体生物杂交治疗将 使我们能够继续进行该项目的R33阶段，在那里我们将测试整体生物杂交的功效 在体外和人源化小鼠模型中根除HIV储库的治疗剂。成功完成 该项目的这一阶段将产生一个新的治疗平台，用于根除持久的艾滋病毒储存库， 将为我们的平台转化为未来临床试验的设计和实施开辟道路。

PROJECT SUMMARY Highly active antiretroviral therapy has reduced morbidity and mortality from HIV/AIDS but does not lead to a cure. The persistence of the virus within latent reservoirs even in well-treated individuals results in a lifelong commitment to these drug regimens. As a consequence, patients remain burdened by co-morbidities and exposed to the negative social issues that come with being HIV-positive. Therefore, there is an urgent need for the development of therapeutic strategies capable of eradicating virus from individuals, which would greatly improve the lives of people living with HIV/AIDS. In response to this need, we propose to combine the actions of latency reversing agents (LRAs), broadly neutralizing antibodies (bnAbs), and activated natural killer (NK) cells within a single therapeutic platform. More specifically, we propose to use bioengineering strategies to design an ensemble biohybrid therapeutic wherein LRAs and bnAbs are packaged within poly(lactic-co-glycolic acid) (PLGA) nanoparticle depots (nanodepots) and then attached on to the surface of NK cells. We anticipate that the co-localization of LRAs with NK cell activation and local bnAb presence will trigger a more effective and coordinated eradication of persistent HIV reservoirs. In the R21 phase of this project, we propose to engineer NK-nanodepots encapsulating LRAs and bnAbs as off-the-shelf biohybrids that retain the phenotype and function of the constituent NK cells and encapsulated LRAs and bnAbs. The realization of a functional ensemble biohybrid therapeutic that successfully coordinates the actions of LRAs, bnAbs, and NK cells will enable us to proceed to the R33 phase of the project where we will test the efficacy of the ensemble biohybrid therapeutic in eradicating the HIV reservoir in vitro and in a humanized mouse model. Successful completion of this phase of the project will result in a novel therapeutic platform for eradicating persistent HIV reservoirs and will open the way for the translation of our platform to the design and conduct of future clinical trials.