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Mouse and mathematical models for HIV-1 suppression through HSPC

通过 HSPC 抑制 HIV-1 的小鼠和数学模型

基本信息

批准号：
8915902
负责人：
IRVIN S.Y. CHEN
金额：
$ 38.1万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2014-09-06 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8915902
关键词：
Address Animal Model Animals Antiviral Therapy B-Lymphocytes Biological Models Biological Process Blood CCR5 gene Case Study Cell Transplants Cells Clinical Research Coupled Cytoprotection Data Disease Engineered Gene Equation Extinction (Psychology)Failure Frequencies Gene Combinations Gene-Modified Genes Genetic Population Study Goals HIV HIV Infections HIV-1 Health Hematopoietic Hematopoietic stem cells Homologous Transplantation Human Immune Immune system In Vitro Individual Infection Kinetics Lead Lentivirus Vector Life Macaca mulatta Measurement Modeling Mus Organism Physiological Processes Population Primates Probability Protocols documentation Publishing RNA Reagent Relative (related person)Site Stem cells Structure System T cell differentiation T-Lymphocyte Testing Therapeutic Thymus Gland Time Tissues Transplantation Treatment Efficacy Viral Load result cellular engineering design dosage gene therapy immune function killings knock-down macrophage mathematical model mouse model nonhuman primate peripheral blood prevent reconstitution small hairpin RNA stem therapeutic gene

项目摘要

DESCRIPTION (provided by applicant): We hypothesize that there exists critical "threshold" levels of repopulation with anti-HIV gene-marked cells above which protection of the immune system from HIV will be successful, and below which, HIV-1 infection will lead to immune system failure. The landmark genetic and population studies showing protection from HIV- 1 in CCR5Δ32 individuals coupled with the remarkable case study demonstrating cure by allogeneic transplantation of CCR5Δ32 hematopoietic stem/progenitor cells (HSPC) has led to numerous transplantation studies using cells engineered to knockdown CCR5 expression. However, determining the critical levels of repopulation after transplant necessary to cure or provide life-long suppression of HIV-1 has not been addressed. Given the expected low levels of gene-marking by anti-HIV-1 gene engineered cells in clinical studies, it is critical to understand the parameters for repopulation at which a minimum level of gene engineered cells protect the individual from HIV-1 infection and restore normal immune function. Establishing and understanding the immune parameters at this "threshold level" is critical for determining experimental conditions for transplant such that repopulation with gene engineered cells is therapeutically effective in preventing HIV-1 from killing the majority of unprotected cells. Testing the above hypothesis is impossible in humans and impractical in non-human primates, so we propose to extend our understanding of repopulation and protection from HIV-1 to a humanized small animal model system. The BLT mouse system is ideal for studying HSPC transplant since unlike other humanized mouse models, the transplanted human HSPC differentiate in the context of a human thymus allowing normal human T-cell differentiation and resulting in robust reconstitution of T-cells (as well as macrophages and Bcells) in peripheral blood and in all the major tissue sites of HIV-1 replication. We recently published in a rhesus macaque transplant model highly analogous to human transplant that thousands of HSPC clones contribute in temporal waves and by diverse lineage potential to repopulation. Like the simian model, we show that repopulation in BLT mice is polyclonal. Transplant can be experimentally manipulated to model different parameters of repopulation with anti-HIV gene engineered cells. To analyze our observations and measurements of T-cells, we will develop mathematical models that capture the key biological processes. Such models will not only help define threshold levels of transplantation, but will also allow one to make systematic predictions under different transplant protocols and experimental conditions. For example, the effects of gene therapeutic reagent and transplantation dosage can be directly investigated. Moreover, by including known equations describing the kinetics of HIV-1 infection, viral loads, the influence of different combinations of antiviral therapies, and the probabilities of extinction and total HIV-1 clearance in organisms can also be explored.

描述（由申请人提供）：我们假设存在抗HIV基因标记细胞再增殖的临界“阈值”水平，高于该水平将成功保护免疫系统免受HIV感染，低于该水平，HIV-1感染将导致免疫系统衰竭。具有里程碑意义的遗传学和群体研究显示，CCR 5 Δ32个体中的HIV- 1保护作用，加上证明通过CCR 5 Δ32造血干/祖细胞（HSPC）的同种异体移植治愈的显著病例研究，已经导致使用经工程改造以敲低CCR 5表达的细胞的许多移植研究。然而，确定移植后治愈或提供终身抑制HIV-1所需的临界再增殖水平尚未得到解决。鉴于抗HIV-1基因工程细胞在临床研究中预期的低水平基因标记，了解最低水平的基因工程细胞保护个体免受HIV-1感染并恢复正常免疫功能的再增殖参数至关重要。建立和理解在这个“阈值水平”的免疫参数对于确定移植的实验条件是至关重要的，使得用基因工程细胞进行再增殖在治疗上有效地防止HIV-1杀死大多数未受保护的细胞。在人类中测试上述假设是不可能的，在非人灵长类动物中也是不切实际的，因此我们建议将我们对HIV-1的再增殖和保护的理解扩展到人源化的小动物模型系统。BLT小鼠系统是研究HSPC移植的理想系统，因为与其他人源化小鼠模型不同，移植的人HSPC在人胸腺的背景下分化，允许正常的人T细胞分化，并导致外周血和HIV-1复制的所有主要组织部位中T细胞（以及巨噬细胞和B细胞）的稳健重建。我们最近发表了一个与人类移植高度相似的恒河猴移植模型，数千个HSPC克隆在时间波和不同的谱系潜力中有助于再增殖。像猿猴模型一样，我们证明BLT小鼠的再增殖是多克隆的。移植可以通过实验操作来模拟抗HIV基因工程细胞的再增殖的不同参数。为了分析我们对T细胞的观察和测量，我们将开发数学模型来捕捉关键的生物过程。这些模型不仅有助于确定移植的阈值水平，而且还允许在不同的移植方案和实验条件下进行系统的预测。例如，可以直接研究基因治疗试剂和移植剂量的影响。此外，通过包括描述HIV-1感染的动力学、病毒载量、还可以探索抗病毒治疗的不同组合，以及生物体中的灭绝和总HIV-1清除的概率。