Functional Role of O-glycosylation of HIV-1

HIV-1 O-糖基化的功能作用

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要众所周知，N连接的碳水化合物包括HIV-1信封质量的很大一部分蛋白质，教条一直是HIV-1包膜蛋白不存在O连接的碳水化合物。这 Desrosiers实验室现在明确表明HIV-1分离株的子集已链接其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通过V3-聚糖类的有效的广泛中和抗体来保护病毒免受识别。我们的结果表明，长V1区域有时会出现，有时没有O连接的糖基化，可能会出现为一种逃避中和抗体的机制，类似于已经迄今为止定义。我们提出的研究将更好地定义V1区域序列的特征可以预测单个序列是否可能是O-糖基化的。我们将确定是否有对阻塞效应的特异性，即一个O-糖基化的V1区域是否有效阻止一个识别 V3-聚糖mAb，但不是另一个，而另一个O-糖基化的V1区域可能具有不同的特异性阻塞效果。我们将使用恒河猴的实验性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区域的选择性劣势和检查可能驱动V1区域延伸和O-糖基化的选择性压力的类型。