A defend and destroy approach to curing HIV

 描述(由申请人提供)：这项提案寻求通过使用自体基因修饰细胞来实现持久的艾滋病毒治愈，方法是“防御和摧毁”。我们的中心前提是，自体细胞可以用于根除艾滋病毒，如果它们是1.基因上使艾滋病毒不会感染的细胞，以及2.通过特定的措施破坏病毒库来增强它们的活性。因此，我们组建了一支具有互补专业知识领域的研究小组，以执行以下具体目标：具体目标1：利用新的基因改造技术来设计具有更强能力摧毁病毒库的抗艾滋病毒免疫系统。(Derrick Rossi，Pi)这项研究利用了Rossi实验室的专业技术，即CRISPR-Cas9基因组编辑系统和修饰的信使核糖核酸技术。具体目标2：增强基因修饰的造血干细胞的植入，降低毒性，保留宿主的生态位条件，在不影响病毒库靶向的情况下，将发病率和成本降至最低。(David Scadden，PI)特定目标3：在艾滋病毒感染和抗病毒治疗的人源化小鼠模型中测试病毒控制和病毒库耗竭的方法。(托德·艾伦，PI)具体目标4：抗艾滋病毒造血干细胞的临床前发展。(CRISPR Treateutics，Rodger Novak，PI)每个AIMS都映射到一个项目，这些项目得到两个核心的支持：A.管理和生物统计学，以及B.人源化小鼠核心生成、治疗和分析感染艾滋病毒并接受三重药物抗逆转录病毒治疗的BLT小鼠。上述四个具体目标中的每一个都可以作为一个具有科学意义的研究项目独立进行。然而，它是实现的协同效应 通过协调实现这些目标，将能够测试根除艾滋病毒感染的多管齐下的战略。如果任何一个项目脱离其他三个项目的背景，就不可能测试这样一套复杂的战略，这些战略共同构成了治疗艾滋病毒感染的“防御和摧毁”方法的平台。因此，只有在两个关键核心的支持下，协同执行这一由四个项目组成的一揽子计划，才能促进对拟议的高度新颖的艾滋病毒治疗战略的测试。

 DESCRIPTION (provided by applicant): This proposal seeks to achieve a durable cure of HIV through the use of autologous gene-modified cells in a 'Defend and Destroy' approach. Our central premise is that autologous cells can be used to eradicate HIV if they are 1. Genetically rendered HIV-uninfectable, and, 2. Enhanced in their activity by specific measures to destroy viral reservoirs. We have therefore assembled a team of investigators with complementary areas of expertise to execute the following specific aims: Specific aim 1: Utilize novel genetic modification technologies to engineer HIV- resistant immune systems with enhanced ability to destroy viral reservoirs. (Derrick Rossi, PI) This takes advantage of expertise in the Rossi lab with the CRISPR- Cas9 genome editing system and modified-mRNA technology. Specific aim 2: Enhance engraftment of gene modified hematopoietic stem cells with reduced toxicity, niche sparing conditioning of the host to minimize morbidity and costs without compromising targeting of viral reservoirs. (David Scadden, PI) Specific aim 3: Test approaches for viral control and vira reservoir depletion in a HIV-infected and anti-viral treated 'humanized' mouse model. (Todd Allen, PI) Specific aim 4: Pre-clinical development of HIV-resistant hematopoietic stem cells. (CRISPR Therapeutics, Rodger Novak, PI) Each aims maps to a project and the projects are supported by two cores: A. Administration and Biostatistics, and, B. Humanized mouse core generating, treating and analyzing BLT mice infected with HIV and treated with triple drug anti-retroviral therapy. Each of the four Specific Aims described above could be conducted independently as a scientifically significant research project. However, it is the synergy achieved through the coordinated accomplishment of these aims that will enable the testing of a multi-pronged strategy for eradicating HIV infection. Testing of such a complex set of strategies, which together represent the platform for a "Defend and Destroy" approach to curing HIV infection, would simply not be possible if any one project were conducted out of the context of the other three. Thus, it is only the concerted execution of this package of four Projects, supported by two critical Cores, that will facilitate testing of the proposed, highly novel strateg for curing HIV.