TOPOLOGICAL ANALYSIS OF HIV-1 ENVELOPE GLYCOPROTEINS

描述：(改编自申请者摘要)信封 糖蛋白是体液免疫的主要靶点。 艾滋病毒-1感染，因此是疫苗开发的一个主要重点。 虽然包膜糖蛋白可以以重组形式表达 具有免疫原性的蛋白质，这些蛋白质似乎是 不足以提供对艾滋病毒-1感染的保护性免疫力。一 致病因素是包膜糖蛋白不能诱导 能够中和主要HIV-1分离株的抗体 效力，尽管它们有能力诱导抗体能够中和 T细胞系适应菌株。尽管存在中和作用 重组蛋白上的抗体表位，效率低下 哪些针对这些表位的抗体是在人类身上产生的 损害这些免疫原的实际效力。理解 这些观察的基础将有助于设计一种新的 免疫原的产生可能更有效地诱导抗体 针对主要的HIV-1分离株。首席调查员的方法 解决问题的关键是更好地理解 包膜糖蛋白，以了解关键的中和抗体表位 都出现在这些蛋白质上。他选择的方法是探测 Gp120和gp160单体和寡聚体的拓扑结构 针对连续和不连续表位的单抗 他能够部分或全部地定义。他不仅要研究 T细胞系适应株的包膜糖蛋白 第一代亚单位疫苗，也是从 初级分离株。除了gp120单体，他还将调查 含有gp120部分的可溶性gp160分子的构象 与gp41的胞外结构域相连，因为这种类型的蛋白质在 被认为是疫苗免疫原。他还将研究构象 表面上最天然的包膜糖蛋白 病毒粒子和受病毒感染的细胞。这些研究的目的是 提高我们对病毒的抗原性和免疫原性的认识 参与产生体液免疫的关键病毒蛋白 抗HIV-1病毒，并可提供信息以促进发展 具有更好性能的新一代艾滋病毒疫苗。

DESCRIPTION : (Adapted from applicant's abstract) The envelope glycoproteins are the principal targets for humoral immunity against HIV-1 infection, and are therefore a major focus of vaccine development. Although the envelope glycoproteins can be expressed as recombinant proteins that are immunogenic, it appears that these proteins are insufficient to provide protective immunity to HIV-1 infection. One contributing factor is the inability of envelope glycoproteins to elicit antibodies able to neutralize primary HIV-1 isolates with significant potency, despite their ability to induce antibodies able to neutralize T-cell line adapted strains. Despite the presence of neutralizing antibody epitopes on the recombinant proteins, the inefficiency with which antibodies against these epitopes are generated in humans may compromise the practical efficacy of these immunogens. Understanding the basis of these observations would facilitate the design of a new generation of immunogens that might better elicit antibodies effective against primary HIV-1 isolates. The principal investigator's approach to the problem is to gain a better understanding of the structure of the envelope glycoproteins, to learn how key neutralizing antibody epitopes are presented on these proteins. The methods he has chosen probe the topology of both monomeric and oligomeric forms of gp120 and gp160 with monoclonal antibodies against continuous and discontinuous epitopes that he is able to partially or totally define. He will study not only the envelope glycoproteins of T-cell line-adapted strains that were used in the first generation of subunit vaccines, but also proteins derived from primary isolates. As well as gp120 monomers, he will investigate the conformation of soluble gp160 molecules that contain the gp120 moiety linked to the ectodomain of gp41, because proteins of this type are under consideration as vaccine immunogens. He will also study the conformation of the envelope glycoproteins in their most native forms on the surfaces of virions and virus-infected cells. These studies are aimed at increasing our understanding of the antigenicity and immunogenicity of key viral proteins involved in the generation of humoral immunity against HIV-1, and may provide information to facilitate the development of new generations of HIV vaccines with improved performance.