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

迄今为止，还没有一种疫苗策略能够成功诱导针对HIV-1的强效广泛中和抗体（BnAb）。体外分析、被动抗体转移研究和RV144疫苗疗效试验中抗体反应分析表明，非中和抗体可能有助于防止HIV-1传播。HIV-1 Env MPER中的三个线性区域，V2和V3被认为是保护性非中和抗体的潜在靶点。我们构建了一种新的重组嗜酸乳杆菌疫苗平台，该平台可以口服给药，并诱导抗原特异性粘膜IgA和全身IgG对抗插入细菌表层蛋白的MPER肽。我们已经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Aim 1将决定粘膜免疫的最佳佐剂，以及反应是t细胞依赖还是独立的。在HLA-DR转基因（DRAG）人源化小鼠模型中，Specific Aim 2将测试表达候选MPER、V2和/或V3表位的重组嗜酸乳杆菌是否能诱导粘膜和全身抗体反应，从而对阴道HIV-1攻击起到保护作用。

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.