Oral Induction of Mucosal and Systemic Antibodies Against HIV-1 gp41 MPER

描述：到目前为止，还没有疫苗策略成功地诱导出针对HIV-1的有效的广谱中和抗体(BNab)。在体外分析、被动抗体转移研究和RV144疫苗效力试验中的抗体反应分析表明，非中和抗体可能有助于防止艾滋病毒-1传播。HIV-1Env MPER、V2和V3上的三个线性区域被认为是保护性非中和抗体的潜在靶点。我们构建了一种新型的重组嗜酸乳杆菌疫苗平台，该平台可以口服，并诱导抗原特异性的粘膜IgA和抗MPER多肽的系统免疫球蛋白插入细菌表层蛋白。我们开发了两种不同的佐剂用于重组嗜酸乳杆菌，IL1和鞭毛蛋白(Flic)。特异性目标1将确定黏膜免疫的最佳佐剂，以及反应是T细胞依赖还是独立。特异性目标2将在人类白细胞抗原DR转基因(Drag)人源化小鼠模型中测试表达候选MPER、V2和/或V3表位的重组嗜酸乳杆菌是否能够诱导粘膜和系统抗体应答，以抵抗阴道感染HIV-1的攻击。

DESCRIPTION: To date, no vaccine strategy has successfully induced potent broadly neutralizing antibodies (BnAb) against HIV-1. In vitro analysis, passive antibody transfer studies and analysis of antibody responses in the RV144 vaccine efficacy trial suggest non- neutralizing antibodies might contribute to protection against HIV-1 transmission. Three linear regions in the HIV-1 Env MPER, V2 and V3 have been implicated as potential targets of protective non-neutralizing antibody. We have constructed a novel recombinant Lactobacillus acidophilus vaccine platform that is orally delivered and induces antigen-specific mucosal IgA and systemic IgG against MPER peptides inserted into the bacterial surface layer protein. We have developed two different adjuvants for use with recombinant L. acidophilus, IL1¿ and flagellin (FliC). Specifi Aim 1 will determine the optimal adjuvant for mucosal immunization and whether responses are T-cell dependent or independent. Specific Aim 2 will test whether recombinant Lactobacillus acidophilus expressing candidate MPER, V2, and/or V3 epitopes can induce mucosal and systemic antibody responses that are protective against vaginal HIV-1 challenge in the HLA-DR transgenic (DRAG), humanized mouse model.