Genetic protection of hematopoietic stem cells for stable HIV control

描述（由申请人提供）：基于造血干/祖细胞（HSPC）的基因治疗有望通过单一治疗长期控制HIV。与HAART一样，必须将多种药物联合收割机有效抑制HIV，防止耐药HIV逃逸突变。该提案的总体假设是，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基因组合稳定引入HSPC将提供终身保护免受HIV感染。抗HIV HSPC基因治疗策略的安全性和有效性，包括抑制HIV，将在最近开发的人骨髓、肝和胸腺（BLT）移植小鼠模型中评价病毒载量的降低和受保护细胞的选择性生长优势以及抗性的预防。具体目标是1）开发新型多管齐下的抗HIV基因治疗性慢病毒载体，并表征治疗试剂，以在体外抑制HSPC及其后代中的HIV感染2）通过在BLT小鼠模型中移植基因工程人HSPC来确定HIV的长期抗基因表达和稳定控制。该方法具有创新性，因为它专注于新型HIV-1靶标HSPC保护和新型强效、广泛的早期和晚期抗HIV组合的开发，不仅在HSPC中，而且在所有潜在靶细胞中最大限度地提高HIV复制的潜力。这项拟议的研究意义重大，因为其结果可能最终导致一种创新的、更有效、更方便、毒性更小、安全和更具成本效益的方法来控制艾滋病毒感染。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.