CHEMOKINE RECEPTORS AND NATURAL HOST RESISTANCE TO SIV

描述(摘自申请者摘要)：越来越多的证据支持 假设HIV/SIV共受体的使用、表达和 监管是艾滋病毒-1传播和艾滋病的关键决定因素 发病机制。例如，32个碱基缺失的纯合性会导致 HIV/SIV进入的关键辅助受体CCR5的表达是一种强大的 阻力系数。这些调查人员最近证明， CCR5调控区携带特定多态的单倍型是 与HIV-1疾病进展速度的改变有关。尽管有这一新的 知识，是不可能在人体上进行实验研究来检验 这一假设，并直接解决遗传和病毒因素的作用 这与HIV的发病机制有关。这些调查人员建议检查 辅受体(CCR5)的表达在疾病进展中的作用 猴免疫缺陷病毒(SIV)模型。具体地说，他们将利用 非洲绿猴(AGM)对SIV的自然抵抗模型 猪尾猕猴对SIV疾病易感性的实验模型。在……里面 在拟议的研究中，调查人员提出了三个具体目标 确定宿主特定的病毒辅助受体使用率和 趋化因子/趋化因子受体表达模式提供了潜在的机制 对SIV介导性疾病的天然抵抗力或易感性。最后，他们 将决定CCR5基因变异的潜在机制 介导对SIV介导性疾病的天然抵抗力或易感性。

DESCRIPTION (from applicant's abstract): There is growing evidence supporting the hypothesisthat differences in HIV/SIV coreceptor usage, expression and regulation are critical determinants of HIV-1 transmission and AIDS pathogenesis. For example, homozygosity for a 32-bp deletion leads to loss of expression of CCR5, a key coreceptor for HIV/SIVentry, serves as a powerful resistance factor. These investigators have recently demonstrated that haplotypes bearing specific polymorphisms in the regulatory regions of CCR5are associated with altered rates of HIV-1disease progression. Despite this new knowledge, it is impossible to conduct experimental studies in humans to test this hypothesis, and to address directly the role of genetic and viral factors that contribute to HIVpathogenesis. These investigators propose to examine the role of coreceptor (CCR5) expression in the progression to disease using the simian immunodeficiency virus (SIV) model. Specifically, they will exploit the model of natural resistance to SIV in African green monkeys (AGM) or the experimental model of disease susceptibility to SIV in pig-tailed macaques. In the proposed studies, the investigators propose three specific aims to determine if host-specific differences in viral coreceptor usage and chemokine/chemokine receptor expression patterns provide potential mechanisms for natural resistance or susceptibility to SIV-mediated disease. Finally, they will determine if potential mechanisms by which genetic variation in CCR5 mediates natural resistance or susceptibility to SIV-mediated disease.