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

描述（由申请人提供）：每年大约有260万新的人类免疫缺陷病毒1型（HIV-1）感染和180万与艾滋病相关的死亡报告。抗艾滋病毒抑制剂可以控制病毒载量，但它们在世界范围内没有广泛使用，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继续传播。约30%的感染者产生保护性抗体反应。这些有效的广泛中和抗体（bNAb）已被发现靶向HIV包膜刺突上的少量保守表位，该刺突由gp120和gp41的三聚体异二聚体组成。将这些表位作为异源抗原呈递到免疫系统提供了最佳的机会来重新引发可以防止HIV感染的bNAb。重新诱导针对gp120和gp41表位的中和抗体的尝试主要集中在将它们作为多肽、工程三聚体、非结构化或结构化插入到异源单体蛋白或病毒样颗粒中。这些研究取得了有限的成功，这表明同源表位的结构环境需要通过控制更广泛的特性来更忠实地再现，包括定向和暴露关键残基和抗体识别结构特征的能力。我们提出了一种新的策略，将单克隆抗体4E10和10E8的gp41表位呈递到嵌合病毒样颗粒（VLPs）上，这些嵌合病毒样颗粒被设计成在其表面呈递特定的结构。这些表位将被精确地移植到昆虫病毒禽舍病毒（FHV）和噬菌体PP7衣壳的高度暴露的表面区域，这两种表面区域都被证明是展示具有生物活性的外源表位和蛋白质结构域的平台，作为多价颗粒阵列，可以诱导有效的抗体反应。然后，这些颗粒将用于给兔子接种疫苗，得到的血清经酶联免疫吸附试验、溶液中病毒捕获和中和试验鉴定。免疫后的兔子有望产生中和抗体，其特异性将在竞争实验中确定。这种在VLPs上进行结构特异性展示的方法如果成功，可能会在HIV疫苗开发方面取得重大进展。

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.