HIV Cure with CCr5 (-) Human IPS Hematopoietic Stem Cells

使用 CCr5 (-) 人 IPS 造血干细胞治愈 HIV

基本信息

批准号：
9052116
负责人：
JAY A LEVY
金额：
$ 69.77万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9052116
关键词：
Address Alleles Anti-Retroviral Agents Autologous Back Berlin Binding Sites Blood Blood Cells CCR5 gene CD34 gene Cell Culture Techniques Cell Transplants Cell physiology Cell surface Cells Clinical Defect Disease Progression Gene Expression Gene Mutation Gene-Modified Genes Genetic Engineering Goals HIV HIV Infections HIV resistance HIV-1 Health Hematopoietic Hematopoietic System Hematopoietic stem cells Human Immune Immunocompromised Host Immunodeficient Mouse In Vitro Individual Laboratories Measures Methods Modification Mus Mutate Mutation Normal Cell Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Population Procedures Resistance Sendai virus Stem cells Surface Testing Tissues Transplantation base cellular engineering cellular transduction humanized mouse immune function in vivo induced pluripotent stem cell mouse model peripheral blood prevent receptor expression reconstitution research study stem transcription activator-like effector nucleases transcription factor vector viral detection

项目摘要

DESCRIPTION: The objective of this proposal is to develop an effective method for providing a "functional cure" for HIV- infected individuals. The approach is based on the observation that subjects lacking CCR5 expression can be highly resistant to HIV infection. Our hypothesis is that hematopoietic CD34+ stem and progenitor cells (HSPC) can be made resistant to HIV infection via mutation in the CCR5 gene. These cells transplanted back to autologous donors will prevent HIV replication and effect a "cure." First, purified human CD34+ cells or peripheral blood mononuclear cells from uninfected individuals will be converted into induced pluripotent stem (iPS) cells by strategies that emphasize non-integrating vectors. These iPS cells will then be genetically modified to have the Δ32bp natural mutation of CCR5 associated with the absence of this receptor expression on the cell surface. Notably, cells naturally lacking CCR5 expression were given to the "Berlin patient" who has no evidence of HIV infection after several years. The iPS-derived CCR5-mutated cells will be converted into CD34+ cells (i.e. iPS-derived CD34+ HSPC) and then differentiated into hematopoietic progeny cells. These cells will be evaluated for resistance to HIV infection and normal cell function in cell culture and after transplantation into humanized mice. The same procedures will be undertaken with genetically modified CD34+ cells from HIV-infected individuals. These studies are directed at optimizing our approaches for providing iPS- derived CD34+ HSPC to HIV- infected individuals to prevent HIV disease progression and potentially establish a "functional cure."

描述：开发一种有效的方法来提供“功能治疗”方法的目的是基于缺乏CCR5表达的受试者对HIV感染具有高度抗性的观察结果。通过CCR5基因中的突变感染HIV。非整合载体 - 将被置的细胞转换为CD34+细胞（即IPS来源的CD34+ HSPC），并评估这些细胞的差异。来自感染的个体的CD34+细胞这些研究指向我们的方法，用于向感染HIV感染的个体提供IPS来源的CD34+ HSPC，以防止HIV疾病的抑制，并有效地建立“功能疗法”。