Humanized mice for Neuro AIDS

描述(由申请人提供)：HIV-1对人类细胞的特异性排除了大多数哺乳动物物种中的病毒感染。这限制了使用小动物模型来研究HIV-1神经发病机制。现有的使用人类异种移植到啮齿动物体内的模型有很大的局限性。我们推测，移植了-/-CD34造血干细胞的NOD/SCID-？C-/-小鼠将在脑内植入人巨噬细胞/小胶质细胞。这些人性化的动物能够慢性感染HIV-1，并产生人类适应性免疫反应。我们将研究人类细胞网络在小鼠大脑中的建立，它们对HIV-1的易感性，以及参与控制HIV-1复制的机制(包括在外周淋巴组织和脑中)。我们还将探索神经元损伤的机制，并将它们与人类HIV-1相关脑病理中涉及的已知因素联系起来。为了验证这一模型，我们将使用两种方法：耗尽人CD8细胞以减少对病毒复制的控制，以及利用人CD40L刺激抗病毒免疫。这些实验将探索该模型的应用，并揭示其使用可能受到的限制。这将是迄今为止最著名的小动物模型，在新的人类免疫系统环境中研究HIV-1的发病机制、治疗方法和疫苗开发。HIV-1对人类细胞的特异性排除了病毒在大多数哺乳动物物种中的感染，并限制了使用小动物模型来研究HIV-1神经发病机制。我们将研究移植人CD34造血干细胞的NOD/SCID-？C-/-小鼠脑内人类细胞网络的建立及其对HIV-1的易感性，以及参与控制HIV-1复制和神经元损伤的机制。这个模型将是最适合神经艾滋病研究的。

DESCRIPTION (provided by applicant): The specificity of HIV-1 for human cells precludes virus infection in most mammalian species. This limits the use of small animal models for the studies of HIV-1 neuropathogenesis. Existing models that use human xenografts into rodents have significant limitations. We hypothesize that NOD/scid-?c-/- mice transplanted with -/- CD34+ hematopoietic stem cells will engraft human macrophages/microglia in the brain. These humanized animals are able to mount chronic HIV-1 infection and develop human adaptive immune responses. We will investigate the establishment of a human cell network in mouse brain, their susceptibility to HIV-1 and the mechanisms involved in the control of HIV-1 replication (both in the peripheral lymphoid tissues and in the brain). We will also explore the mechanisms of neuronal damage and correlate them with known factors involved in human HIV-1-associated brain pathology. To validate this model we will use two approaches: depletion of human CD8+ cells to diminish control of viral replication, and stimulation of anti-viral immunity by human CD40L. These experiments will explore the application of the model and unmask possible restrictions for its use. It will be the best known small animal model as of today, to study HIV-1 pathogenesis, therapeutics and vaccine development in a novel human immune system setting. The specificity of HIV-1 for human cells precludes virus infection in most mammalian species and limits the use of small animal models for the studies of HIV-1 neuropathogenesis. We will investigate the establishment of a human cell network in the brain of NOD/scid-?c-/- mice transplanted with human CD34+ hematopoietic stem -/- cells, their susceptibility to HIV-1, the mechanisms involved in the control of HIV-1 replication and neuronal damage. This model will be the best suited for NeuroAIDS research.