Functional Role of O-glycosylation of HIV-1

HIV-1 O-糖基化的功能作用

• 批准号: 10363617
• 负责人: Ronald C Desrosiers
• 金额: $ 44.81万
• 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/10363617
• 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; Persons; 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.

项目总结/摘要 虽然已知N-连接的碳水化合物构成HIV-1包膜质量的显著部分， 对于HIV-1包膜蛋白，教条是O-连接的碳水化合物不存在于HIV-1包膜蛋白中。的 Desrosiers实验室现已明确表明，HIV-1分离株的一个子集具有O-连锁 糖蛋白的V1区。此外，这种O-连接的碳水化合物是 能够保护病毒不被V3-聚糖类的有效广泛中和抗体识别。我们 结果表明，长的V1区，有时没有O-连接的糖基化，可以出现， 一种逃避中和抗体的机制，类似于已经被发现的V3-聚糖单克隆抗体， 定义至今。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是O-糖基化的。我们将确定是否有 阻断效应的特异性，即一个O-糖基化的V1区是否有效地阻断一个O-糖基化的V1区的识别。 V3-聚糖mAb而不是另一种，而不同的O-糖基化V1区可能对其具有不同的特异性。 阻塞效应我们将使用实验性SHIV感染恒河猴，以检查是否有 在不存在这种抗体的情况下对这种长O-糖基化V1区的选择性不利， 检查可能驱动V1区的延伸和O-糖基化的选择性压力的类型。