Generation of gp96SIVIg/TNFSF13 and gp96SIVIg/TNFSF15 vaccinesVaccines

对HIV和SIV的保护需要粘膜免疫。我们开发了非传统的安全的 基于通过热休克蛋白-伴侣蛋白gp 96或通过HPV递送SIV抗原的疫苗 假病毒粒子。我们已经确定，这两种疫苗产生强大的阴道和 直肠免疫应答是多表位特异性的和多功能的， 抗体和T细胞应答，包括CD 8 CTL。我们假设并将确定疫苗将 改变对阴道SIV攻击的反应，具有保护猕猴免于SIV疾病的效果。我们 进一步假设通过同时分析（i）宫颈阴道的粘膜屏障功能 粘液，（ii）阴道/子宫颈中的先天性和（iii）适应性免疫应答，（iv）基因表达谱， 蛋白质组学（v）磷蛋白和（vi）质膜蛋白，我们将能够与系统的工具， 生物学鉴定与保护阴道SIV相关的转录和信号通路 挑战.最后，由于两种疫苗方法在分子和机制上不同，我们 假设如果将它们组合在主要加强策略中并另外与 gp 120蛋白和佐剂。这将是确定的。虽然我们乐观地认为，疫苗单独或在 联合用药将保护阴道免受SIV攻击，我们的研究也将提供信息， 如何进一步改进我们的疫苗方法，如果需要更强的保护。

Protection from HIV and SIV requires mucosal immunity. We have developed unconventional and safe vaccines based on the delivery of SIV antigens via heat shock protein-chaperone gp96 or by HPV pseudovirion particles. We have already established that the two vaccines generate powerful vaginal and rectal immune responses that are polyepitope specific and multifunctional and generate antigen specific antibody and T cell responses, including CD8 CTL. We hypothesize and will determine that the vaccines will modify the response to vaginal SIV challenge with the effect of protecting macaques from SIV disease. We further hypothesize that by analyzing simultaneously (i) mucosal barrier function of the cervicovaginal mucus, (ii) innate and (iii) adaptive immune responses in vagina/cervix, (iv) gene expression profiles, proteomic (v) phosphoproteins and (vi) plasma membrane proteins, we will be able with the tools of systems biology identify transcriptional and signaling pathways that correlate with protection from vaginal SIV challenge. Finally, since the two vaccine approaches are distinct molecularly and mechanistically, we hypothesize that they will be synergistic if combined in a prime boost strategy and additionally combined with gp120 protein and adjuvant. This will be determined. While we are optimistic that the vaccines singly or in combination will be protective against vaginal SIV challenge, our studies also will provide the information how to further improve our vaccine approach, if even stronger protection is required.