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：
8024559
负责人：
Phillip Wayne Berman
金额：
$ 70.88万
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/8024559
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）：每天大约有 14,000 例新感染病例，迫切需要开发一种安全有效的 HIV 疫苗。然而，迄今为止测试的所有策略都未能实现这一目标。因此，如果要开发出安全有效的疫苗来预防艾滋病毒感染，就需要新的策略。最近于 2008 年 3 月在 NIH 举行的 HIV 疫苗峰会列出了对于开发 HIV 疫苗至关重要的九个高度优先的研究目标。这笔拨款中提出的工作直接涉及列出的九个最高研究优先事项之一，即：“确定为什么广泛中和抗体（bNAb）不常见以及如何引发它们”。我们解决这个问题的新方法基于令人惊讶的初步结果，该结果表明 HIV gp120 上的切割位点是高度保守的，这些切割位点被细胞内和分泌的酶识别，这些酶已知对抗原加工、肿瘤生长和寄生虫感染很重要。令人惊讶的是，这些位点也位于或邻近对受体结合或中和抗体的结合重要的特定氨基酸。由于病毒变异率很高，这些位点一定是由于强烈的选择压力而得以保留，可能是为了逃避免疫反应。在本提案中，我们希望使 HIV 包膜蛋白上的这些保守切割位点失活，以产生蛋白酶抗性包膜糖蛋白。然后我们将表达兔子免疫原性研究所需的数量。将检测所得血清中是否存在广泛中和抗体。我们假设这些位点的失活将保留重要的表位，这些表位在能够刺激强大的免疫反应之前通常会在体内降解。保留这些表位应该使我们能够重新定向针对 HIV 包膜蛋白的免疫反应，从而改善广泛中和抗体的形成。这些实验有可能解释为什么迄今为止测试的疫苗很难引发中和抗体，以及多年来困扰该领域的其他观察结果。公共卫生相关性：在这些研究中，我们提出了一种开发 HIV 疫苗抗原的新方法。我们将尝试通过抗原加工酶识别的保守位点的突变来提高广泛中和抗体识别的包膜蛋白上表位的免疫原性。