Prophylactic oral vaccination for SIV and SHIV infections and AIDS prevention

总结 该建议旨在扩展我们先前的研究，在这些研究中，我们实现了显著的全身和粘膜 用SIV DNA-rMVA方法进行口腔和肠道免疫后的细胞应答。这些 免疫接种对SIV暴露和感染有两个重要影响：1.肠道免疫提供了 显著保护免受感染，但不保护免受疾病进展; 2.口腔免疫 在攻毒后随访期间未观察到AIDS发展， 超过50%的动物在经历了一次病毒感染后，将病毒复制控制在无法检测的血液水平。 病毒血症的峰值，并且明显清除感染，因为在CD 8 + T细胞耗尽后没有观察到反弹。 在这里，我们建议在食蟹猴中研究抗SIV和SHIV口服免疫方法， 刺激细胞免疫应答，以前通过口服免疫实现，和持久的抗Env IgG 和伊加滴度，以前散发或缺失，全身和粘膜部位发生HIV暴露， 人类该建议的目标如下：一。评价由1. pSIVvaxE 543 DNA，用gp 140（smE 543）Env和rMVA加强，2. pSIVvaxE 543 DNA + SIVgag 239和 SIVenvsmE 543重组OPV（统称为SIV-OPV），和3. SIV-OPV单独比较其刺激 细胞介导和体液免疫系统和粘膜部位，其中HIV传播发生在人类， 以及它们是否在食蟹猴中提供针对异源SIVmac 251感染和疾病的保护 （CM）。二.评价三种免疫调节剂对全身和粘膜细胞介导的免疫和体液免疫的刺激作用， 包括SHIVBG 505 DNA + SIVgag 239-OPV和HIV Env-OPV的方案，其中最后一个组分中的Env是线性的 组1中的HIVBG 505 gp 140、组2中的SOSIP-gp 140 BG 505和组3中的V1-V2 BG 505支架，以及是否 这些应答在CM中提供了针对异源SHIVAD 8感染和疾病的保护; III.评价 用重复SHIV-OPV免疫观察到的抗HIV Env抗体亲和力成熟的程度。在这些 实验中，我们将评估抗SIV或SHIV免疫反应的机制特征以及相关性 保护免受感染和疾病，重点是分析肠粘膜反应和病毒载量， 水库，并可能根除感染后。

SUMMARY This proposal is designed to extend our previous studies where we achieved significant systemic and mucosal cellular responses after oral cavity and intestinal immunizations with a SIV DNA-rMVA approach. These immunizations had two important impacts on SIV exposure and infection: 1. the intestinal immunization provided significant protection from infection but no protection from disease progression; 2. the oral cavity immunization provided significant protection from disease with no AIDS development observed during the post-challenge follow up and with more than 50% of the animals controlling virus replication to undetectable blood levels after experiencing a peak of viremia, and apparently clearing the infection, as no rebound was observed after CD8+ T-cell depletion. Here we propose to investigate in Cynomolgus macaques anti-SIV and SHIV oral immunization approaches aimed at stimulating cellular immune responses, previously achieved via oral immunization, and persistent anti-Env IgG and IgA titers, previously sporadic or missing, systemically and at mucosal sites where HIV exposure occurs in humans. The goal sof the proposal are the following: I. To evaluate how oral immunization regimens composed of 1. pSIVvaxE543 DNA, boosted with gp140(smE543) Env and rMVA, 2. pSIVvaxE543 DNA + SIVgag239 and SIVenvsmE543 recombinant OPVs (collectively called SIV-OPV), and 3. SIV-OPV alone compare in their stimulation of cell mediated and humoral immunity systemically and at mucosal sites where HIV transmission occurs in humans, and whether they provide protection from heterologous SIVmac251 infection and disease in Cynomolgus macaques (CM). II. To evaluate stimulation of systemic and mucosal cell-mediated immunity and humoral immunity by three regimes that include SHIVBG505 DNA + SIVgag239-OPV and HIV Env-OPV, where Env in this last component is linear HIVBG505 gp140 in Group 1, a SOSIP-gp140 BG505 in Group 2, and a V1-V2 BG505 scaffold in Group 3, and whether these responses provide protection from heterologous SHIVAD8 infection and disease in CM; III. To evaluate the extent of anti-HIV Env antibody affinity maturation observed with repeated SHIV-OPV immunization. During these experiments we will evaluate mechanistic characteristics of the anti-SIV or SHIV immune response and correlates of protection from infection and disease, with focus on the analysis of intestinal mucosa responses and viral loads, viral reservoirs, and possibly eradication post infection.