SCID HU MODEL FOR HIV INFECTION OF THE CNS

HIV痴呆症(HIVD)在HIV感染的临床过程中可以发挥重要作用。HIVD被认为影响了20%-30%的艾滋病毒感染患者。由于血管周围间隙的巨噬细胞和实质中的小胶质细胞被认为是HIV在中枢神经系统(NS)感染的主要部位，这些细胞类型可能在导致HIVD的致病事件中发挥关键作用。在这项研究中，我们建议建立一个小动物模型，在其中我们可以研究中枢神经系统中这些细胞类型的HIV感染以及这种感染的致病机制。为此，我们开发了一种新的SCID-HU模型，SCID-HU BTL(bone-Thy/Liv-Lapnode)，它允许在小鼠中枢神经系统中种植人巨噬细胞在血管周围空间(脉络丛和脑膜)，以及人小胶质细胞在实质中。我们将利用我们在SCID-Hu模型开发、人类造血干细胞(HSC)生物学和HSC基因修饰方面的专业知识，实现以下具体目标：(1)确定在SCID-Hu BTL(bone-Thy/Liv-Lapnode)小鼠体内种植中枢神经系统的人巨噬细胞和小胶质细胞的组织和祖细胞来源；(2)检测SCID-Hu BTL小鼠中枢神经系统对HIV感染和发病的趋向性要求；(3)在SCID-Hu BTL模型中研究神经发病的非感染性机制及其遗传学基础。

HIV dementia (HIVD) can play a significant role in the clinical course of an HIV infection. HIVD is thought to affect 20-30% of patients with HIV infections. Because macrophages in the perivascular space and microglial in the parenchyma are thought to be the primary sites of HIV infection in the central nervous system (NS), these cell types are likely to play a critical role with pathogenic events that lead to HIVD. In this study we propose to develop a small animal model in which we can study HIV infection of these cell types in the CNS and pathogenic mechanisms that are a consequence of this infection. Towards that end we have developed a novel SCID-hu model, SCID-hu BTL (Bone-Thy/liv-Lymph node), that allows seeding of the murine CNS with human macrophages in the perivascular spaces (choroid plexus and meninges) and human microglia in the parenchyma. We will take advantage of our expertise with the development of SCID-hu models, the biology of human hematopoietic stem cells (HSC) and gene modification of HSC to carry out the following specific goals: (1) Determine the tissue and progenitor source of human macrophages and microglia that seed the CNS in SCID-hu BTL (Bone-Thy/liv-Lymph node) mice, (2) Examine tropism requirements for HIV infection and pathogenesis in the CNS of SCID-hu BTL mice and (3) Examine non-infectious mechanisms of neuropathogenesis and their genetic basis in the SCID-hu BTL model.