Refocusing the Immune Response to the HIV Envelope Glycoprotein

重新关注 HIV 包膜糖蛋白的免疫反应

基本信息

批准号：
8215739
负责人：
Phillip Wayne Berman
金额：
$ 70.1万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA CRUZ
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-15 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8215739
关键词：
Address Amino Acids Antibodies Antigen Presentation Pathway Antigen-Presenting Cells Antigens Binding Binding Sites Biological Assay Biological Preservation Blocking Antibodies Cathepsin L Cathepsins Development Drug Formulations Enzymes Epitopes Evaluation Genes Glycoproteins Goals Grant HIV HIV Envelope Protein gp120 HIV Infections HIV Receptors HIV envelope protein HIV vaccine Histocompatibility Antigens Class II Human Immune response Immunization In Vitro Individual Infection Mammalian Cell Maps Mass Spectrum Analysis Measures Membrane Molecular Conformation Mutagenesis Mutation Oryctolagus cuniculus Parasitic infection Peptide Hydrolases Play Production Proteins Proteolysis Research Priority Research Proposals Resistance Role SIV Sequence Analysis Serum Site Structure Techniques Testing United States National Institutes of Health Vaccine Antigen Vaccines Variant Virus Work antigen processing base env Gene Products expression vector falls immunogenicity improved in vivo monomer mutant neutralizing antibody neutralizing monoclonal antibodies nonhuman primate novel novel strategies pressure prevent public health relevance receptor binding research study success tumor growth vaccine evaluation

项目摘要

DESCRIPTION (provided by applicant): With approximately 14,000 new infections per day, there is an urgent need to develop a safe and effective HIV vaccine. However, all of the strategies tested to date have fallen short of this goal. Thus, new strategies are required if the development of a safe and effective vaccine to prevent HIV infection is ever to be realized. A recent HIV Vaccine Summit held at NIH in March 2008 listed nine high priority research objectives essential for the development of an HIV vaccine. The work proposed in this grant directly addresses one of the nine highest research priorities listed, namely: "Determine why broadly neutralizing antibodies (bNAbs) are uncommon and how they can be elicited". Our new approach to this problem is based on surprising preliminary results showing that cleavage sites on HIV gp120, recognized by intracellular and secreted enzymes known to be important for antigen processing, tumor growth, and parasitic infection, are highly conserved. Surprisingly, these sites are also located at, or adjacent to, specific amino acids important for receptor binding or the binding of neutralizing antibodies. Because of the high rate of virus variation, these sites must have been conserved as the result of strong selective pressure, possibly to evade the immune response. In this proposal we wish to inactivate these conserved cleavage sites on HIV envelope proteins to create protease resistant envelope glycoproteins. We will then express these in quantities required for rabbit immunogenicity studies. The resulting sera will be assayed for the presence of broadly neutralizing antibodies. We postulate that inactivation of these sites will preserve important epitopes that are normally degraded in vivo before they are able to stimulate robust immune responses. Preservation of these epitopes should allow us to redirect the immune response to HIV envelope proteins in a way that improves the formation of broadly neutralizing antibodies. These experiments have the potential to explain why it has been so difficult to elicit neutralizing antibodies with the vaccines tested to date, as well as other observations that have perplexed the field for many years. PUBLIC HEALTH RELEVANCE: In these studies we propose a new approach to the development of HIV vaccine antigens. We will attempt to improve the immunogenicity of epitopes on the envelope protein recognized by broadly neutralizing antibodies by mutation of conserved sites recognized by antigen processing enzymes.

描述（由申请人提供）：每天约有14,000个新感染，迫切需要开发安全有效的HIV疫苗。但是，迄今为止测试的所有策略都没有达到这一目标。因此，如果要实现安全有效的疫苗以防止艾滋病毒感染，则需要采取新的策略。 2008年3月在NIH举行的HIV疫苗峰会最近举行的一次HIV疫苗峰会列出了九个高优先研究目标，这对于开发HIV疫苗必不可少。本赠款中提出的工作直接解决了列出的九项最高研究优先级之一，即：“确定为什么广泛中和抗体（BNAB）并不常见，以及如何引起它们”。我们解决此问题的新方法是基于令人惊讶的初步结果，表明HIV GP120上的裂解位点是由已知对抗原加工，肿瘤生长和寄生虫感染非常重要的细胞内和分泌酶认可的。出乎意料的是，这些位点也位于或与特异性氨基酸相邻或相邻，对于受体结合或中和抗体的结合很重要。由于病毒变异率很高，因此这些位点必须是由于强烈的选择压力而保守的，可能会逃避免疫反应。在此提案中，我们希望在HIV包膜蛋白上灭活这些保守的切割位点，以产生抗蛋白酶的包膜糖蛋白。然后，我们将以兔子免疫原性研究所需的数量来表达这些。将对所得的血清进行广泛中和抗体的存在。我们假设这些位点的灭活将保留通常在体内降解的重要表位，然后才能刺激强大的免疫反应。这些表位的保存应使我们能够以改善广泛中和抗体形成的方式重定向对HIV包膜蛋白的免疫反应。这些实验有可能解释为什么很难通过迄今为止测试的疫苗以及其他观察结果引起中和抗体，这些抗体多年来一直困扰着该领域。公共卫生相关性：在这些研究中，我们为开发HIV疫苗抗原的开发提出了一种新方法。我们将尝试通过通过抗原加工酶识别的保守位点的突变来识别抗体，以提高表位上的表位上的免疫原性。