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

描述（由申请人提供）：每年报告约有260万人感染1型人类免疫缺陷病毒（HIV-1），180万人死于艾滋病相关疾病。抗HIV抑制剂可以控制病毒载量，但它们在世界范围内并不广泛使用，并且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继续传播。大约30%的感染者会产生保护性抗体反应。已经发现这些有效的广泛中和抗体（bNAb）靶向HIV包膜刺突上的少量保守表位，所述刺突由gp 120和gp 41的三聚体异二聚体组成。将这些表位作为异源抗原呈递给免疫系统提供了重新引发可以保护免受HIV感染的bNAb的最佳机会。重新引发针对gp 120和gp 41表位的中和抗体的尝试集中于将它们呈现为肽、工程化三聚体以及异源单体蛋白或病毒样颗粒中的非结构化或结构化插入物。这些研究取得的成功有限，这表明需要通过控制更广泛的特性选择来更忠实地复制同源表位的结构环境，包括定向和暴露关键残基和结构特征以进行抗体识别的能力。我们提出了一种新的策略，用于在嵌合病毒样颗粒（VLP）上呈递单克隆抗体4 E10和10 E8的gp 41表位，所述嵌合病毒样颗粒（VLP）经工程改造以在其表面上呈递特定结构。表位将被精确地移植到昆虫病毒Flock House病毒（FHV）和噬菌体PP 7衣壳的充分表征和高度暴露的表面区域上，这两种衣壳都被证明是用于将生物活性外源表位和蛋白质结构域展示为诱导有效抗体应答的多价颗粒阵列的平台。然后将颗粒用于接种家兔，并通过ELISA、溶液中病毒捕获和中和试验对所得血清进行表征。预期免疫的兔产生中和抗体，其特异性将在竞争实验中确定。如果成功，所提出的在VLP上使用结构特异性展示的方法可能会导致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.