CHEMOKINE RECEPTORS AND NATURAL HOST RESISTANCE TO SIV

描述（来自申请人摘要）：越来越多的证据支持 假设HIV/SIV辅助受体的使用、表达和 监管是HIV-1传播和艾滋病的关键决定因素 发病机制例如，32-bp缺失的纯合性导致缺失。 CCR 5是HIV/SIV进入的关键辅助受体， 阻力系数这些调查人员最近证明， 在CCR 5调控区具有特异性多态性的单倍型是 与HIV-1疾病进展速度的改变有关。尽管这个新 知识，不可能在人类身上进行实验研究来测试 这一假设，并直接解决遗传和病毒因素的作用， 导致艾滋病发病机制。这些调查人员建议检查 共受体（CCR 5）表达在疾病进展中的作用， 猴免疫缺陷病毒（SIV）模型。具体来说，他们将利用 非洲绿色猴（AGM）对SIV的天然抗性模型或 猪尾猕猴对SIV疾病易感性的实验模型。在 在拟议的研究中，研究人员提出了三个具体目标， 确定病毒辅助受体使用的宿主特异性差异， 趋化因子/趋化因子受体表达模式提供了潜在的机制 对SIV介导的疾病的天然抵抗力或易感性。最后他们 将确定CCR 5基因变异的潜在机制 介导对SIV介导的疾病的天然抗性或易感性。

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.