NATURAL HOST RESISTANCE TO SIVAGM INDUCED DISEASE

非洲绿色猴中的猴免疫缺陷病毒（SIVagm） 是研究宿主对自然- 发生病毒。 虽然病毒、细胞和细胞病变表型[e] 组织嗜性、病毒载量、宿主免疫应答和宿主遗传因素 都被认为与艾滋病的发展有关，但很少有 会 已知关于对慢病毒感染的疾病的天然抗性， 非洲非人灵长类动物。 SIV agm模型将用于定义 病毒和宿主对疾病和直接免疫的天然抗性决定因素 评估病毒异质性和boh变异的预期等级， 自然和非自然宿主，以更好地了解病毒的进化。 本文的具体目标如下：1.为了比较病毒 负载存在于自然感染的非洲绿色猴和 实验性感染的长尾猕猴。 病毒载量是重要的 是人类疾病进展的标志物，并被认为反映了 细胞杀伤、周转和免疫耗竭的水平。 初步证据 表明自然感染的非洲猴子的病毒载量很高， 没有临床疾病表明病毒 发病机制 我们将病毒载量的时间变化定义为 CD 4功能与疾病状态的关系。 2. 定义和比较病毒 天然和非天然宿主物种的异质性和病毒进化 我们将使用异源双链迁移率测定（HMA）首先解决范围 血浆病毒的复杂性。 然后我们将选择单个样本 用于直接测序，以研究血浆、PBMC和组织中的病毒变异 隔间 非同义词的积累率研究 同义替换可以提供重要的线索，在理解 病毒与宿主共同进化，缺乏致病性。 3.到 检查SIVagm在自然和非自然宿主中的细胞病变性质。 在自然宿主中的发病机制可能与 SIVagm诱导易感小鼠细胞病理学的能力差异 细胞 β-趋化因子受体被认为是作为细胞因子的共受体起作用。 病毒进入并部分地限定细胞和组织向性。 C的研究 SIVagm病毒之间的受体使用可能有助于理解 HIV和SIVagm的致病性。 4.为了进一步研究一种致病的 SIVagm感染的动物模型。 我们将进一步完善和定义 猪尾猕猴的SIVagm致病模型。 重点将指向 研究SIVagm的组织特异性变体及其在免疫应答中的作用， 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.