NATURAL HOST RESISTANCE TO SIVAGM INDUCED DISEASE

非洲绿猴体内的猴免疫缺陷病毒(SIVagm) 是研究寄主对自然-赤霉病抗性的重要资源 正在发生的病毒。当病毒、细胞和病毒的细胞病变表型 组织嗜性、病毒载量、宿主免疫反应和宿主遗传因素 都被认为与艾滋病的进展有关，S很少被认为是 LL 已知慢病毒感染对疾病的天然抵抗力 非洲非人灵长类动物。SIV agm模型将用于定义 病毒和宿主天然抗病和直接抗病的决定因素 评估病毒的异质性和Boh的预期变异率 自然宿主和非自然宿主可以更好地了解病毒的进化。 在本课题中，具体目标如下：1.比较病毒 在自然感染的非洲绿猴和 实验感染了辫尾猕猴。病毒载量是一个重要的 人类疾病进展的标志，并被认为反映了 细胞杀伤、周转和免疫衰竭的水平。初步证据 这表明自然感染的非洲猴子的病毒载量很高 没有临床疾病提示病毒的根本差异 发病机制。我们将病毒负载中的临时门户变异定义为 CD4细胞功能与疾病状态的关系。2.定义和比较病毒 自然和非自然寄主物种的异质性和病毒进化 我们将使用异双工移动性分析(HMA)首先解决范围 血浆病毒内部的复杂性。然后我们将挑选单独的样品 用于直接测序以研究血浆、PBMC和组织中的病毒变异 车厢。非同义词的累积速率研究 同义替换可能为理解这一现象提供重要线索 病毒和宿主的共同进化以及缺乏致病性。3.至 检查SIVagm在自然和非自然宿主中的细胞病变性质。 自然寄主在发病机制上的差异可能与 SIVagm诱导易感人群细胞病变能力的差异 细胞。β-趋化因子受体被认为是血管内皮生长因子的辅助受体 病毒进入并在一定程度上可以定义细胞和组织的嗜性。关于C语言的研究 SIVagm病毒之间受体的使用可能有助于理解差异 HIV和SIVagm的致病性。4.进一步调查一种病原体 SIVagm感染的动物模型。我们将进一步细化和定义 尾辫猕猴的SIVagm致病模型。重点将定向 SIVagm的组织特异性变异体及其在组织中的作用研究进展 疾病过程。

Simian immunodeficiency viruses in African green monkeys (SIVagm) constitute an important resource for studing host resistance to naturally- occuring viruses. While the cytopathic phenoty[e of the virus, cell and tissue tropism, viral load, host immune responses and host genetic factors are all thought to be associated with progression to AIDS, very little is s ll known concerning natural resistance to disease for lentiviral infections of african nonhuman primates. The SIV agm model will be used to define viral and host determinants of natural resistance to disease and to directl assess viral heterogenceity and the expected rated of variation of boh the natural and unnatural host to be better understand viral evolution. In this propodal, the specific aims are as follows: 1. To compare the viral load present in both naturally infected African green monkeys and experimentally infected pigtailed macaques. Viral load is an important marker for disease progression in humans and is postulated to reflect the level of cell killing, turnover, and immune depletion. Preliminary evidenc suggests that the viral load in naturally infected african monkeys is high without clinical disease suggesting fundamental differences in viral pathogenesis. We will define temportal variation in virral load as a function of CD4 munber and disease state. 2. To define and compare viral heterogeneity and viral evolution in the natural and unnatural host species We will use heteroduplex mobility assays (HMA) to first address the range of complexity within plasma virus. We will then select individual samples for direct sequencing to study viral variation in plasma, PBMC and tissue compartments. The study of accumulation rates of non-synonymous to synonymous substitutions may provide important clues in the understanding of co-evolution of virus and host and the lack of pathogenicity. 3. To examine the cytopathic nature of SIVagm in the natural and unnatural hosts. Deifferences in pathogenesis in the natural host may coincide with differences in the ability of SIVagm to induce cytopathology in susceptible cells. Beta-chemokine receptors are thought to function as co-receptors fo viral entry and in part may define cell and tissue tropism. The study of c receptor usage among SIVagm viruses may aid in understanding differential pathogenicity of HIV and SIVagm. 4. To further investigate a pathogenic animal model for SIVagm infection. We will further refine and define the SIVagm pathogenic model in pigtailed macaques. Emphasis will directed toward the study of tissue-specific variants of SIVagm and their role in th disease process.