SCID HU MODEL FOR HIV INFECTION OF THE CNS

HIV痴呆（HIVD）在HIV感染的临床过程中起着重要作用。据认为，HIVD影响20-30%的艾滋病毒感染患者。由于血管周围间隙中的巨噬细胞和实质中的小胶质细胞被认为是中枢神经系统（NS）中HIV感染的主要部位，因此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，我们建议开发一个小动物模型，在其中我们可以研究HIV感染的这些细胞类型在中枢神经系统和致病机制，是这种感染的后果。为此，我们开发了一种新的SCID-hu模型，SCID-hu BTL（骨-Thy/肝-淋巴结），其允许在血管周围空间（脉络丛和脑膜）中接种人巨噬细胞和在实质中接种人小胶质细胞。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中接种CNS的人巨噬细胞和小胶质细胞的组织和祖细胞来源（骨-Thy/肝-淋巴结）小鼠，（2）检查HIV感染的嗜性要求和SCID-hu BTL小鼠CNS中的发病机理，和（3）检查SCID-hu BTL小鼠CNS中神经发病机理的非感染性机制及其遗传基础。hu BTL模型

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.