Functional Role of O-glycosylation of HIV-1

HIV-1 O-糖基化的功能作用

• 批准号: 10012154
• 负责人: Ronald C Desrosiers
• 金额: $ 46.1万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10012154
• 关键词: Amaze; Amino Acids; Antibodies; Antibody Response; Automobile Driving; B-Lymphocytes; Biology of HIV Infection; Carbohydrates; Categories; Cell Line; Characteristics; Collection; Data Collection; Databases; Dependovirus; Deposition; Disadvantaged; Evolution; HIV Envelope Protein gp120; HIV-1; HIV-2; Individual; Infection; Journals; Knock-out; Laboratories; Length; Link; Macaca mulatta; Malawi; Membrane Glycoproteins; Monkeys; Monoclonal Antibodies; Nature; Paper; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Plasma; Play; Polysaccharides; Predictive Factor; Prevention; Publishing; RNA; Recombinants; Role; Serine; Site; Specificity; Testing; Therapeutic Uses; Threonine; Time; Variant; Virion; Virus; Work; adeno-associated viral vector; course sequence; env Gene Products; glycosylation; interest; knowledge base; man; neutralizing antibody; neutralizing monoclonal antibodies; pressure; recombinant virus; resistance mutation; simian human immunodeficiency virus; vector; virology

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.

项目概要/摘要 虽然已知 N 连接碳水化合物占 HIV-1 包膜质量的很大一部分 HIV-1 包膜蛋白中不存在 O-连接碳水化合物。这 Desrosiers 实验室现已明确表明，HIV-1 分离株的一个子集具有 O 型连锁 gp120 表面糖蛋白 V1 区域上的碳水化合物。此外，这种 O-连接碳水化合物是 能够保护病毒免遭 V3 聚糖类强效广泛中和抗体的识别。我们的 结果表明，长 V1 区域（有时带有 O-连接糖基化，有时不带有 O-连接糖基化）可以出现为 一种逃避中和抗体的机制，类似于 V3-聚糖单克隆抗体 迄今为止定义的。我们提出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被 O-糖基化。我们将判断是否有 阻断效应的特异性，即一个 O-糖基化 V1 区域是否有效阻断一个 O-糖基化 V1 区域的识别 V3-聚糖单克隆抗体，但不同的 O-糖基化 V1 区域可能对其具有不同的特异性 阻塞效应。我们将利用恒河猴的实验性 SHIV 感染来检查是否存在 在没有此类抗体的情况下，对如此长的 O-糖基化 V1 区的选择性不利 检查可能驱动 V1 区域延伸和 O-糖基化的选择压力类型。