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CD34+血压调节基因是否修饰干细胞（HSC）以抵抗HIV感染以及移植CD8+的基因修饰 T细胞可以协同起作用，以阻止ART会议后的病毒反弹和有效地放射性HIV储存库。具体来说，我们将利用项目2的专业知识（新型HSC植入条件方案）和项目1和4（强大的基因编辑）包括CRISPR/CAS9在内的方法有效修改和植入HSC和自体 HSC移植方法中的CD8+ T细胞。我们将在体内测试这些概念最近开发的CD34+ HSC衍生的人型BLT小鼠模型，该模型概括了HIV 感染和人类对艾滋病毒的免疫力，以实现“捍卫和摧毁”的两个阶段艾滋病毒治愈策略：i）通过淘汰移植的细胞来防止未来的艾滋病毒感染 CD34+造血干细胞中的HIV共受体CCR5（HSC）； ii）增强能力自体，成熟的CD8+ T细胞，以查找并破坏残留的HIV感染细胞操纵与效应功能，粘膜和储层归巢相关的基因以及目标细胞识别。我们假设限制病毒传播的合并方法同样，通过自体CD8+ T细胞反应增强免疫清除率实现HIV感染功能性治疗的潜力。