Engineering T cells to Provide Durable Control of HIV-1 Replication

改造 T 细胞以提供 HIV-1 复制的持久控制

• 批准号: 8899244
• 负责人: James L Riley
• 金额: $ 233.51万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-10 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8899244
• 关键词: Anti-Retroviral Agents; Antigen Receptors; Antiviral Agents; Autologous; CCR5 gene; CD4 Positive T Lymphocytes; CD8B1 gene; CXCR4 gene; Cell Therapy; Cells; Chronic; Clinic; Clinical; Clinical Data; Clinical Trials; Collaborations; Cost Sharing; Detection; Development; Dose; Drops; Economic Burden; Elements; Enabling Factors; Engineering; Evolution; Future; Genetic; Genetic Engineering; Goals; HIV; HIV Infections; HIV-1; Highly Active Antiretroviral Therapy; Human; Immune system; Immunity; Individual; Industry; Infection; Infection Control; Infection prevention; Interruption; Lentivirus Vector; Link; Medical Economics; Modeling; Molecular; Monitor; Mus; Pathway interactions; Patients; Peptides; Phase I Clinical Trials; Plasma; Population; Positioning Attribute; Program Research Project Grants; Protocols documentation; Research; Research Infrastructure; Resistance; Resources; Safety; Sampling; Scientist; Signal Transduction; T cell response; T cell therapy; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Therapy trial; Time; Viral; Viral Load result; Viremia; Virus; Work; Zinc Fingers; arm; base; chimeric antigen receptor; design; design and construction; exhaustion; experience; follow-up; genotoxicity; improved; in vivo; industry partner; inhibitor/antagonist; insight; interdisciplinary approach; medical schools; mouse model; next generation; novel; novel strategies; nuclease; peptide C34; phase 1 study; programs; public health relevance; receptor; research clinical testing; research study; response; restoration; safety testing; success; trafficking; vector; zinc finger nuclease

 DESCRIPTION (provided by applicant): Our long-term goal is to build an HIV-resistant immune system that controls HIV-1 replication in the absence of HAART. Based on prior studies in the field, it is likely that both enhanced HIV-specific immunity, as well as a population of CD4 T cells resistant to HIV infection will be required to achieve this goal. In collaboration with Sangamo Biosciences, we recently performed a clinical trial that infused T cells rendered HIV resistant by zinc finger nuclease disruption of the CCR5 coreceptor. The viral load of one of the individuals in this study dropped below the limit of detection in the absence of HAART, suggesting that infused HIV-1 resistant CD4 T cells are capable of controlling HIV-1 replication. Another benefit of our last IPCP was the co-development (Penn and Sangamo) of a potent antiviral construct called C34-CXCR4. In this application, we will determine the clinical utility o this construct, and by comparing our clinical data from the CCR5 ZFN study, we hope to gain important insight into the key factors required to protect CD4 T cells in vivo and to better study how partial restoration of the CD4 T cell response enables control of HIV-1 replication. Traditionally, throughout our academic/industry program project grants, a consistent theme has been to concurrently test one concept in the clinic while performing research that will serve as the basis and rationale for the next clinical trial. A key component of this application is the continuation of that tradition. The elements of our proposal are: 1) A Phase I Study of C34-CXCR4 Peptide-Modified CD4 T Cells in HIV-1 (Project 1, Tebas [Penn]): This project will test the safety and feasibility of infusing autologous T cells expressing a C34-CXCR4 fusion construct in HIV-1 infected individuals. 2) C34-modified Coreceptors as Potent Trans-dominant Inhibitors of HIV-1 Entry (Project 2, Holmes [Sangamo]): This project will utilize Sangamo's zinc finger nuclease technology to target C34-CXCR4 into the CXCR4 locus in primary human T cells, limiting the genotoxicity and the possibility of vector silencing. Efforts wll also be made to understand how this construct is so effective against all strains of HIV-1 and to improve its activity if possible. 3) Designing T cells to Functionally Cure HIV-1 infection (Project 3: Riley [Penn]). This project seeks to engineer HIV-1 resistant, HIV-1 specific CD4 T cells that can control HIV-1 replication long-term in the absence of HAART in a humanized mouse model of HIV-1 infection. 4) Programming Long-Term Durable HIV-1 Specific T cell Responses (Project 4: Wherry [Penn]). This project aims to molecularly define the pathways that promote durability in human CD4 T cells using state of the art profiling technology and an array of relevant models to probe factors that enable CD4 T cells to maintain high levels of activity for prolonged periods of time. The Program is supported by 2 Cores: Core A is the administrative Core (PI, Riley); Core B is the Sequencing and Viral Evolution Core (PI, Bushman). In addition, our Program takes advantage of existing School of Medicine, ITMAT, and CFAR Cores to promote cost sharing and avoid duplication of resources.

 描述(申请人提供)：我们的长期目标是建立一个抗HIV免疫系统，在没有HAART的情况下控制HIV-1的复制。根据该领域以前的研究，很可能既增强了艾滋病毒特异性免疫力，也增强了CD4 为了实现这一目标，将需要具有抗艾滋病毒感染能力的T细胞。在与Sangamo Biosciences的合作下，我们最近进行了一项临床试验，注入T细胞，通过破坏CCR5辅助受体的锌指核酸酶来产生艾滋病毒耐药性。在没有HAART的情况下，这项研究中其中一个人的病毒载量降到了检测极限以下，这表明输注的抗HIV-1的CD4T细胞能够控制HIV-1的复制。我们上一次IPCP的另一个好处是共同开发(宾夕法尼亚大学和桑加莫大学)一种名为C34-CXCR4的有效抗病毒结构。在这项应用中，我们将确定该构建物的临床效用，并通过比较我们来自CCR5 ZFN研究的临床数据，希望获得对体内保护CD4T细胞所需的关键因素的重要见解，并更好地研究部分恢复CD4T细胞反应如何能够控制HIV-1复制。传统上，在我们的学术/行业项目资助中，一个一贯的主题是在临床上同时测试一个概念，同时进行研究，作为下一次临床试验的基础和理论基础。这一应用的一个关键组成部分是对这一传统的延续。我们建议的内容包括：1)在HIV-1中进行C34-CXCR4肽修饰的CD4T细胞的第一阶段研究(项目1，Tebas[Penn])：该项目将测试在HIV-1感染者中输注表达C34-CXCR4融合结构的自体T细胞的安全性和可行性。2)C34修饰的辅助受体作为HIV-1进入的有效反式显性抑制剂(项目2，Holmes[Sangamo])：该项目将利用Sangamo的锌指核酸酶技术将C34-CXCR4靶向原代人类T细胞的CXCR4基因座，以限制遗传毒性和载体沉默的可能性。还将努力了解这种结构如何对所有HIV-1毒株如此有效，并在可能的情况下提高其活性。3)设计T细胞从功能上治愈HIV-1感染(项目3：Riley[Penn])。该项目致力于在人源化的HIV-1感染小鼠模型中设计抗HIV-1的、HIV-1特异性的CD4T细胞，在没有HAART的情况下长期控制HIV-1的复制。4)规划长期持久的HIV-1特异性T细胞反应(项目4：Wherry[Penn])。该项目旨在使用最先进的图谱技术和一系列相关模型，从分子上确定促进人类CD4T细胞耐久性的途径，以探索使CD4T细胞在较长时间内保持高水平活动的因素。该计划由两个核心支持：核心A是管理核心(PI，Riley)；核心B是测序和病毒进化核心(PI，Bushman)。此外，我们的计划利用现有的医学院、ITMAT和CFAR核心来促进成本分担和避免资源重复。