An AIDS Vaccine Cocktail Composed of 2 Conserved Conformational Immunogens

描述（由申请人提供）：Gp 160是HIV的主要表面蛋白，由2个关键亚基gp 120和gp 41组成。在任一亚基中，都可以发现疫苗开发工作的感兴趣区域; gp 120和gp 41都含有在感染过程中发挥基本生物化学作用的区域或亚结构域。疫苗诱导抗体靶向gp 120和gp 41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疫苗，这种疫苗可以激发识别gp 160高度保守和功能性部分的抗体。HIV包膜蛋白gp 160中至少有2个高度保守的功能区。1是gp 120中的C4结构域。C4结构域被认为是gp 120的一个组成部分，它在HIV感染过程的第一步介导病毒包膜与细胞结合的能力。如果C4结构域中没有1个特定的氨基酸，HIV将不会感染细胞。gp 160的第二个高度保守的功能部分是gp 41中的区域，该区域是4 E10的表位，4 E10是一种广泛有效的单克隆抗体，可阻断大多数HIV毒株和进化枝感染易感细胞。4 E10的表位被认为在融合过程中起主要作用，该融合过程通过字面上将受体细胞膜与HIV表面膜融合来完成感染过程。这两个区域都是独特的，因为它们在所有HIV毒株和进化枝中高度保守。因此，由在人体中激发抗C4结构域和4 E10样抗体反应的鸡尾酒组成的免疫原将是朝着设计安全有效的HIV疫苗的目标的巨大进步。十多年来，我们一直在开发肽化学方法，以诱导线性合成肽呈现新的构象。在这项研究中，我们将专注于测试来自gp 120的C4结构域和来自gp 41的4 E10表位的2种新的构象保守的生物材料的混合物作为抗HIV的潜在疫苗。在家兔中，已发现这2种材料可独立引发与gp 160发生反应的抗体，并将一起进行最佳免疫应答试验。成功的免疫原阻断HIV感染的商业机会是巨大的。 该项目旨在创造艾滋病毒疫苗成分，以抵抗艾滋病毒变异的趋势并逃避正常的免疫反应。这种新的疫苗成分应该有助于在全世界防治艾滋病毒感染。

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.