This proposal is to develop engineered exosome CRISPR/saCas9 cargo to target HIV genomes and program exosome delivery to latently-infected cell types for HIV eradication.

 描述（由申请人提供）：HIV-1仍然是一个世界性的健康问题，仅在美国每年估计就有约50，000例新发病例。虽然抗逆转录病毒疗法已经将艾滋病毒感染的面貌从绝症改变为慢性可控制的疾病，但它并不能恢复受感染者的正常免疫功能或寿命。艾滋病病毒可以潜伏在体内的几个部位，包括中枢神经系统，在那里它建立了病毒库，尽管治疗，它仍然持续存在。一种靶向基因组编辑方法，允许从受感染的细胞中精确和有效地删除整合的HIV DNA，这将是HIV治愈的一个重大进展。我们建议开发装载CRISPR/Cas9基因组编辑机制的工程化外泌体，旨在靶向潜在感染细胞中的整合HIV DNA。这些工程化的外泌体也将使用表面配体展示技术进行编程，以解决囊泡粘附并将货物递送至感兴趣的细胞类型。该项目的总体目标是创建一个系统，其中个性化的外泌体穿梭可以用作治疗递送载体，以根除病毒细胞库中的HIV。

 DESCRIPTION (provided by applicant: HIV-1 continues to be a world-wide health problem with an estimated incidence of ~50,000 new cases each year in the United States alone. While antiretroviral therapy has changed the face of HIV infection from terminal illness to a chronic manageable disease, it does not restore a normal immune function or lifespan in infected subjects. A cure to permanently eliminate the virus from the body is yet to be found. HIV can remain latent in several sites within the body including the CNS where it establishes viral reservoirs and continues to persist despite treatment. A targeted genome editing approach that allows for precise and efficient deletion of integrated HIV DNA from the infected cell will be a significant advancement toward HIV cure. We propose to develop engineered exosomes loaded with CRISPR/Cas9 genome editing machinery designed to target integrated HIV DNA in latently-infected cells. These engineered exosomes will also be programmed using surface ligand display technologies to address the vesicles to adhere and deliver the cargo to cell types of interest. The overall goal of this project is to create a system where personalized exosome shuttles can be utilized as therapeutic delivery vehicles to eradicate HIV in viral cellular reservoirs.