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

生物材料增强的 NK 细胞可改善 HIV 病毒库的消除

基本信息

批准号：
10247828
负责人：
Conrad Russell Young Cruz
金额：
$ 48.57万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-03 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10247828
关键词：
AIDS/HIV problem Activated Natural Killer Cell Adoptive Transfer Anatomy Animals Antibodies Apoptosis Autologous Avidin Biocompatible Materials Biological Assay Biomedical Engineering Biotin CD4 Positive T Lymphocytes Cell Therapy Cells Chemistry Clinical Trials Coupled Coupling Encapsulated Engineering Ensure Exposure to FCGR3B gene Formulation Freeze Drying Future Glycolates HIV HIV Seropositivity HIV therapy HIV vaccine Highly Active Antiretroviral Therapy Human Immune Immune response Immune system Immunity Immunodeficient Mouse In Vitro Individual Infection Interleukin-15 Interleukin-2 Kinetics Link Maleimides Mediating Morbidity - disease rate NK Cell Activation Natural Killer Cells Patients Penetration Pharmaceutical Preparations Phase Phenotype Proteins Public Health Regimen Research Role Sampling Scheme Site Source Sulfhydryl Compounds Surface Testing Therapeutic Time Tissues Translations Vaccines Viral Viral Cytopathogenic Effect Viral reservoir Virus Virus Diseases antibody-dependent cell cytotoxicity arm base bryostatin cell bank comorbidity cytotoxic design efficacy testing engineered NK cell exhaust humanized mouse improved in vivo insight latent HIV reservoir mortality mouse model nanoparticle natural killer cell protein 44-kDa neutralizing antibody novel therapeutic intervention novel therapeutics prevent prostratin reconstitution response social therapeutic development vaccine trial viral rebound

项目摘要

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.

项目总结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，但不会导致解药。即使在接受良好治疗的个体中，病毒也会在潜伏的宿主中持续存在，从而导致终生对这些药物疗法的承诺。因此，患者仍然背负着合并症和暴露于艾滋病毒阳性带来的负面社会问题。因此，迫切需要开发能够从个人身上根除病毒的治疗策略，这将极大地改善艾滋病毒/艾滋病患者的生活。针对这一需要，我们建议将这些行动结合起来潜伏期反转剂(LRA)、广谱中和抗体(BNAbs)和激活的自然杀伤细胞(NK) 单个治疗平台中的细胞。更具体地说，我们建议使用生物工程策略来设计一种整体生物杂化疗法，其中LRAs和bNAbs被包装在聚乳酸-羟基乙酸中酸)(PLGA)纳米粒储存库(纳米储存库)，然后附着在NK细胞表面。我们期待着 LRAs与NK细胞活化和局部bNab存在的共同定位将触发更有效的以及协调一致地根除持久的艾滋病毒携带者。在这个项目的R21阶段，我们建议将LRA和bNAbs包装为保留表型的现成生物杂交物的工程NK-纳米库 NK细胞和囊化LRAs、bNAbs的功能。一种功能的实现成功协调LRA、bNAbs和NK细胞活动的整体生物混合疗法将使我们能够继续进行项目的R33阶段，在那里我们将测试整体生物杂交的有效性在体外和人源化小鼠模型中根除艾滋病毒蓄积物的治疗方法。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宿主和将为我们的平台转化为未来临床试验的设计和进行铺平道路。