Genetic protection of hematopoietic stem cells for stable HIV control

描述（由申请人提供）：基于造血干细胞/祖细胞（HSPC）的基因疗法有望通过一次治疗长期控制HIV。与HAART一样，必须联合使用多种药物才能有效抑制艾滋病毒并预防耐药艾滋病毒逃逸突变体。该建议的总体假设是，将能够抑制HIV病毒生命周期的多个早期和晚期步骤的高效抗HIV基因组合稳定地引入HSPC，将提供终生的HIV感染保护。将在新近建立的人骨髓、肝脏和胸腺（BLT）移植小鼠模型中评估其对降低病毒载量和保护细胞选择性生长优势以及预防耐药性的作用。具体目的是：1)开发新型多管齐下的抗HIV基因治疗慢病毒载体，并鉴定治疗试剂，在体外抑制HSPC及其后代的HIV感染；2)通过基因工程人HSPC移植BLT小鼠模型，确定HIV的长期抗基因表达和稳定控制。该方法是创新的，因为它专注于新的HIV-1靶点HSPC保护和开发新的有效的，广泛的早期和晚期抗HIV组合，最大限度地提高HIV在HSPC和所有潜在靶细胞中的复制潜力。这项拟议中的研究意义重大，因为其结果可能最终导致一种比目前可用的更创新、更有效、更方便、毒性更小、更安全、更经济有效的控制艾滋病毒感染的方法。长期目标是推进基于HSPC的基因治疗研究，并在提供一种通过单一治疗稳定控制HIV的新疗法方面取得快速进展。

DESCRIPTION (provided by applicant): Hematopoietic stem/progenitor cell (HSPC) based gene therapy holds great promise to provide long-term control of HIV with a single treatment. Like HAART, it is essential to combine multiple drugs to effectively suppress HIV and prevent drug resistant HIV escape mutants. The overall hypothesis of this proposal is that stable introduction of highly potent combinations of anti-HIV genes capable of inhibiting multiple early and late steps of HIV viral lifecycle into HSPC will provide lifelong protection from HIV infection The safety and efficacy of anti-HIV HSPC gene therapy strategies, including inhibition of HIV, lowering of viral load and selective growth advantage of protected cells and prevention of resistance will be evaluated in the recently developed human bone marrow, liver and thymus (BLT) transplanted mouse model. Specific aims are 1) To develop novel multi-pronged anti-HIV gene therapeutic lentiviral vectors and characterize therapeutic reagents to inhibit HIV infection in HSPC and their progeny in vitro 2) To determine the long-term anti-gene expression and stable control of HIV through genetically engineered human HSPC transplant in the BLT mouse model. The approach is innovative because it focuses on novel HIV-1 target HSPC protection and the development of novel potent, broad-range early stage and late stage anti-HIV combinations, maximizing the potential to HIV replication not only in HSPC but also all potential target cells. The proposed research is significant because the results may ultimately lead to an innovative, more effective, more convenient, less toxic, safe and more cost effective way of controlling HIV infection than is currently available. The long-term goal is to advance HSPC based gene therapy research and make rapid progress towards providing a new therapy that leads to stable control of HIV by a single treatment.