Leveraging Genetic Engineering Towards a Functional Cure of HIV Infection

利用基因工程实现艾滋病毒感染的功能性治愈

基本信息

批准号：
8897540
负责人：
TODD M ALLEN
金额：
$ 45.21万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8897540
关键词：
Activities of Daily Living Animal Model Antisense RNA Autologous Berlin Boston CCR5 gene CD34 gene CD4 Positive T Lymphocytes CD8B1 gene Catalytic RNA Cell Transplants Cells Chemokine (C-C Motif) Receptor 5 Clinical Clustered Regularly Interspaced Short Palindromic Repeats Cytomegalovirus DNA Sequence Alteration Development Disease remission Engraftment Evaluation Future Gene-Modified Genes Genetic Genetic Engineering HIV HIV Infections Hematopoietic stem cells Herpesviridae Homing Human Immune Immune response Immunity Immunization Individual Infection Interruption Intervention Knock-out Low Prevalence Macaca mulatta Mammalian Cell Mediating Mississippi Modeling Mus Natural Immunity Patients Population RNA Interference Recombinants Regimen Reporting Residual state SELL gene SIV Safety Staging Stem cell transplant Stem cells Surface T cell response T-Lymphocyte Technology Testing Time Transplantation Vaccines Viral Viral Load result Viremia Virus Virus Latency Work allotransplant antiretroviral therapy aptamer combat conditioning exhaustion genetic manipulation immune clearance improved in vivo mouse model novel novel strategies prevent receptor zinc finger nuclease

项目摘要

Project 3 seeks to determine whether gene modification of transplanted CD34+ hemotopoietic stem cells (HSCs) to resist HIV infection combined with gene modification of transplanted CD8+ T cells can function coordinately to block viral rebound following sessation of ART and effectively eradicate HIV reservoirs. Specifically, we will leverage the expertise of Project 2 (novel HSC engraftment conditioning regimens) and Projects 1 and 4 (powerful gene-editing approaches including CRISPR/Cas9) to efficiently modify and engraft HSCs and autologous CD8+ T cells within an HSC transplant approach. We will test these concepts in vivo utilizing the recently developed CD34+ HSC-derived humanized BLT mouse model that recapitulates HIV infection and human immunity to HIV to accomplish the two stages of a `Defend and Destroy” HIV cure strategy: i) defend transplanted cells against future HIV infection by knocking out the HIV co-receptor CCR5 in CD34+ hematopoietic stem cells (HSCs); and ii) enhance the capacity of autologous, mature CD8+ T cells to find and destroy residual HIV infected cells by manipulating genes associated with effector function, mucosal and reservoir homing, and target cell recognition. We hypothesize that the combined approach of limiting viral spread while simultaneously enhancing immune clearance by autologous CD8+ T cell responses has the potential to achieve a functional cure of HIV infection.

项目3旨在确定移植的CD34+造血功能是否受到基因修饰干细胞（HSC）结合移植的 CD8+ 基因修饰来抵抗 HIV 感染 T 细胞可以协调发挥作用，阻止 ART 治疗后的病毒反弹，具体来说，我们将利用项目 2 的专业知识。（新颖的 HSC 移植调理方案）以及项目 1 和 4（强大的基因编辑方法（包括 CRISPR/Cas9）有效修饰和移植 HSC 和自体细胞我们将利用 HSC 移植方法在体内测试这些概念。最近开发的 CD34+ HSC 衍生的人源化 BLT 小鼠模型可概括 HIV 感染和人类对艾滋病毒的免疫力，以完成“防御和摧毁”的两个阶段 HIV 治疗策略：i) 通过消除 CD34+ 造血干细胞 (HSC) 中的 HIV 共受体 CCR5 增强能力；自体成熟 CD8+ T 细胞，通过以下方式发现并消灭残留的 HIV 感染细胞操纵与效应器功能、粘膜和储库归巢以及靶标相关的基因我们追求限制病毒传播的综合方法。同时通过自体 CD8+ T 细胞反应增强免疫清除实现艾滋病毒感染功能性治愈的潜力。