An AIDS Vaccine Cocktail Composed of 2 Conserved Conformational Immunogens

由 2 种保守构象免疫原组成的艾滋病疫苗混合物

• 批准号: 7164476
• 负责人: Frank A. Robey
• 金额: $ 25.59万
• 依托单位: ARIAVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7164476
• 关键词: AIDS vaccines; HIV infections; antibody; antigens; human; peptides; protein sequence

DESCRIPTION (provided by applicant): Gp160, the major surface protein on HIV, is composed of 2 key subunits, gp120 and gp41. Within either subunit there can be found regions of interest for vaccine development efforts; both gp120 and gp41 contain zones or sub domains that play fundamental biochemical roles in the infection process. There also are key points of contact for targeting highly conserved regions of gp120 and gp41 with vaccine-inducing antibodies. These areas will remain well preserved despite most of the virus undergoing rapid mutational changes. So, a major goal of HIV vaccine design is to develop a vaccine that elicits antibodies that recognize the highly conserved and functional parts of gp160. At least 2 highly conserved functional regions can be found in the HIV envelope protein, gp160. 1 is the C4 domain found in gp120. The C4 domain is considered to be an integral component of gp120 that mediates the ability of the viral envelope to bind to cells in the first step of the HIV infection process. Without 1 specific amino acid in the C4 domain, HIV will not infect cells. A second highly conserved functional part of gp160 is the area in gp41 that is the epitope for 4E10, a broadly effective monoclonal antibody that blocks most strains and clades of HIV from infecting susceptible cells. The epitope for 4E10 is believed to play a major role in the fusion process that completes the infection process by literally fusing the recipient cell membrane with the HIV surface membrane. Both regions are unique in-so-far-as they are very highly conserved among all strains and clades of HIV. As such, an immunogen composed of a cocktail that elicits anti C4 domain and 4E10-like antibody responses in humans would be a huge advance toward the goal of designing a safe and effective vaccine against HIV. For over a decade, we have been developing methods in peptide chemistry to induce linear synthetic peptides to assume new conformations. For this study, we will focus exclusively on testing a cocktail of 2 new conformationally conserved biomaterials from the C4 domain of gp120 and the 4E10 epitope from gp41 as a potential vaccine against HIV. In rabbits, the 2 materials have been found to independently elicit antibodies that react with gp160 and they will be tested together for optimal immune responses. The commercial opportunities for a successful immunogen that acts to block HIV infection are enormous. This project is geared toward creating vaccine components for HIV that will resist the tendency of HIV to mutate and elude normal immune responses. Such novel vaccine components should be useful to combat HIV infection throughout all of the world.

描述(申请人提供)：Gp160是HIV的主要表面蛋白，由两个关键亚单位gp120和gp41组成。在任一亚单位内，都可以找到疫苗开发工作的感兴趣区域；gp120和gp41都包含在感染过程中发挥基本生化作用的区域或亚域。用疫苗诱导抗体靶向gp120和gp41的高度保守区域也有关键的接触点。尽管大多数病毒正在经历快速突变，但这些区域将保持完好。因此，HIV疫苗设计的一个主要目标是开发一种能够诱导抗体识别gp160高度保守和功能部分的疫苗。在HIV包膜蛋白gp160中至少有两个高度保守的功能区。1是在gp120中发现的C4结构域。C4结构域被认为是gp120的一个组成部分，在HIV感染过程的第一步，它介导了病毒被膜与细胞结合的能力。如果C4区域没有1个特定的氨基酸，HIV就不会感染细胞。Gp160的第二个高度保守的功能部分是gp41中的区域，这是4E10的表位，4E10是一种广泛有效的单抗，可以阻止大多数HIV毒株和分支感染敏感细胞。4E10的表位被认为在融合过程中发挥了重要作用，融合过程通过将受体细胞膜与HIV表膜融合来完成感染过程。到目前为止，这两个区域都是独一无二的，因为它们在所有艾滋病毒毒株和分支中都非常保守。因此，由鸡尾酒组成的免疫原在人类中引发抗C4结构域和4E10样抗体反应，将是朝着设计安全有效的艾滋病毒疫苗的目标迈进的一大步。十多年来，我们一直在开发多肽化学方法，以诱导线性合成肽呈现新的构象。在这项研究中，我们将专门测试来自gp120的C4结构域的两种新的构象保守的生物材料和来自gp41的4E10表位的鸡尾酒作为潜在的HIV疫苗。在兔子身上，这两种材料已经被发现可以独立地诱导与gp160反应的抗体，它们将一起进行测试，以获得最佳的免疫反应。一种成功的免疫原能阻断艾滋病毒感染的商业机会是巨大的。 该项目致力于创造艾滋病毒疫苗成分，以抵抗艾滋病毒变异和逃避正常免疫反应的趋势。这些新的疫苗成分应该有助于在全世界抗击艾滋病毒感染。