Developing a structure-specific HIV vaccine using chimeric virus-like particles

描述(申请人提供)：每年报告的人类免疫缺陷病毒1型(HIV-1)新感染病例约为260万例，艾滋病相关死亡病例约为180万例。抗艾滋病毒抑制剂可以控制病毒载量，但它们并不是在全球范围内广泛使用，也不能消除或预防感染。因此，需要一种有效的疫苗来防止艾滋病毒的持续传播。大约30%的感染者会产生保护性抗体反应。这些有效的广谱中和抗体(BNAb)被发现针对HIV包膜尖峰上的少量保守表位，包膜尖峰由gp120和gp41的三聚体异源二聚体组成。将这些表位作为异源抗原呈现给免疫系统，提供了重新诱导能够预防HIV感染的bNAb的最佳机会。重新诱导针对gp120和gp41表位的中和抗体的尝试主要集中在以多肽、工程三聚体和异源单体蛋白或病毒样颗粒中的非结构化或结构化插入的形式呈现它们。这些研究取得的成功有限，表明需要通过控制更广泛的属性选择来更真实地再现同源表位的结构环境，包括定位和揭示抗体识别的关键残基和结构特征的能力。我们提出了一种新的策略，在嵌合病毒样颗粒(VLP)上呈现单抗4E10和10E8的gp41表位，该嵌合病毒样颗粒被设计成在其表面呈现特定的结构。这些表位将被精确地嫁接到昆虫病毒群屋病毒(FHV)和噬菌体PP7衣壳的特征良好和高度暴露的表面区域，这两个已被证实的平台都可以作为多价颗粒阵列展示具有生物活性的外源表位和蛋白质结构域，从而诱导强大的抗体反应。然后，这些颗粒将被用来接种兔子，所产生的血清经过酶联免疫吸附试验、溶液中病毒捕获和中和试验进行表征。免疫的兔子有望产生中和抗体，其特异性将在竞争实验中确定。建议的方法使用VLP上的结构特异性显示，如果成功，可能会导致HIV疫苗开发的重大进展。

DESCRIPTION (provided by applicant): There are approximately 2.6 million new infections of human immunodeficiency virus type 1 (HIV-1) and 1.8 million AIDS-related deaths reported annually. Anti-HIV inhibitors are available that can control viral loads, but they are not widely available worldwide and do not eliminate or prevent infection. Thus, an effective vaccine is needed to prevent the continuing spread of HIV. A protective antibody response is generated in about 30% of infected individuals. These potent broadly neutralizing antibodies (bNAb) have been found to target a small number of conserved epitopes on the HIV envelope spike, which is composed of trimeric heterodimers of gp120 and gp41. Presenting these epitopes as heterologous antigens to the immune system provides the best opportunity to re-elicit bNAb's that can protect against HIV infection. Attempts to re-elicit neutralizing antibodies against the gp120 and gp41 epitopes has focused on presenting them as peptides, engineered trimers, and unstructured or structured insertions in heterologous monomeric proteins or virus-like particles. These studies have met with limited success indicating that the structural environment of the cognate epitopes needs to be more faithfully reproduced using control over a wider selection of properties, including the ability to orient and expose key residues and structural features for antibody recognition. We propose a novel strategy for presenting the gp41 epitopes of monoclonal antibodies 4E10 and 10E8 on chimeric virus-like particles (VLPs) engineered to present specific structures on their surfaces. The epitopes will be precisely grafted onto well characterized and highly exposed surface regions of the insect virus Flock House virus (FHV) and bacteriophage PP7 capsids, both proven platforms for displaying biologically active foreign epitopes and protein domains as polyvalent particulate arrays that induce potent antibody responses. The particles will then be used to vaccinate rabbits and the resulting sera characterized by ELISA, in-solution virus capture and neutralization assays. The immunized rabbits are expected to generate neutralizing antibodies whose specificity will be determined in competition experiments. The proposed approach using structure-specific display on VLPs, if successful, could lead to a significant advance in HIV vaccine development.