Functional Role of O-glycosylation of HIV-1

项目摘要/摘要 虽然已知N-连接的碳水化合物占HIV-1包膜质量的很大一部分 蛋白质方面，人们一直认为HIV-1包膜蛋白中没有O-连接的碳水化合物。这个 DesRosiers实验室现在明确地表明，HIV-1分离株的一个子集具有O-连接 他们的gp120表面糖蛋白的V1区域上的碳水化合物。此外，这种O-连接的碳水化合物是 能够保护病毒不被V3-葡聚糖类的强效广中和抗体识别。我们的 结果表明，长的V1区域，有时没有O-连接的糖基化，可以出现为 一种逃避中和抗体的机制，类似于V3-葡聚糖单克隆抗体 到目前为止已定义。我们建议的研究将更好地定义V1区序列的特征 预测单个序列是否可能是O-糖基化的。我们会确定是否有 对阻断效应的特异性，即一个O-糖基化的V1区域是否有效地阻断一个 不同的O-糖基化的V1区可能对其具有不同的特异性 阻挡效应。我们将用实验性的SIV感染恒河猴来检查是否有 在没有这种抗体的情况下，如此长的O-糖基化V1区具有选择性劣势 检查可能驱动V1区域延长和O-糖基化的选择性压力的类型。

Project Summary/Abstract While N-linked carbohydrate is known to comprise a significant portion of the mass of HIV-1 envelope protein, the dogma has been that O-linked carbohydrate is absent from HIV-1 envelope protein. The Desrosiers laboratory has now shown unambiguously that a subset of HIV-1 isolates have O-linked carbohydrate on the V1 region of their gp120 surface glycoprotein. Furthermore, this O-linked carbohydrate is able to shield virus from recognition by potent broadly-neutralizing antibodies of the V3-glycan class. Our results suggest that long V1 regions, sometimes with sometimes without O-linked glycosylation, can emerge as a mechanism to escape neutralizing antibodies similar to the V3-glycan monoclonal antibodies that have been defined to date. Our proposed studies will better define the characteristics of V1 region sequences that are predictive of whether an individual sequence is likely to be O-glycosylated. We will determine whether there is specificity to the blocking effects, i.e. whether one O-glycosylated V1 region potently blocks recognition by one V3-glycan mAb but not another while a different O-glycosylated V1 region may have different specificities to its blocking effects. We will use experimental SHIV infection of rhesus monkeys to examine whether there is selective disadvantage to such long O-glycosylated V1 regions in the absence of such antibodies and to examine the types of selective pressure that may drive elongation and O-glycosylation of V1 regions.