VACCINE USING HIV/SIV ENV, GAG, NEF & TAT ADENOVIRUS WITH PROTEIN BOOSTING

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们先前证明，复制能力强的Ad-SIV重组Prime/Protein Boost方案可诱导强烈的免疫原性和对SIVmac251恒河猴的强大、持久的保护。此外，国产TAT疫苗对食蟹猴的SHIV89.6P攻击具有强大的保护作用，而国产、灭活疫苗或载体TAT疫苗未能在恒河猴身上产生类似的保护效果。在这里，我们问的是，用复制的Ad-HIVtat和Tat蛋白增强免疫恒河猴是否会引起对SHIV89.6P的保护。我们还评估了TAT/env方案，添加了Ad-HIVenv重组和包膜蛋白Boost来测试包膜抗体是否会增强急性期保护作用。此外，为了期望细胞免疫增强慢性病毒血症的控制，我们测试了多基因组：Ad-HIVtat、-HIVenv、-SIVgag和-SIVnef重组体以及Tat、Env和Nef蛋白。所有方案都是免疫原性的。在ELISPOT反应(Env GT Gag GT Nef GT Tat)和抗体效价(Env GT Tat GT Nef GT Gag)中观察到了层次结构。在静脉注射SHIV89.6P攻击后，所有猕猴都被感染。与对照组相比，仅服用TAT的组没有看到保护措施，这证实了之前的报道。然而，多基因组钝化急性病毒血症约1log(p=0.017)，与对照组相比，多基因组和TAT/env组的慢性病毒血症分别减少了3log和4logs(多基因，p=0.0003；TAT/env，p 0.0001)。与多基因组相比，TAT/env的显著降低(p=0.014)与TAT和env结合抗体有关。由于攻击前的抗Env抗体缺乏SHIV89.6P中和活性，其他功能性抗Env和抗TAT活性正在研究中，TAT和Env免疫原之间可能存在协同作用。 我们正在继续监测剩余的动物，以评估不同群体之间可能存在的生存差异。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We previously demonstrated that replication-competent Ad-SIV recombinant prime/protein boost regimens elicit potent immunogenicity and strong, durable protection of rhesus macaques against SIVmac251. Additionally, native Tat vaccines have conferred strong protection against SHIV89.6P challenge of cynomolgus monkeys, while native, inactivated, or vectored Tat vaccines have failed to elicit similar protective efficacy in rhesus macaques. Here we asked if priming rhesus macaques with replicating Ad-HIVtat and boosting with Tat protein would elicit protection against SHIV89.6P. We also evaluated a tat/env regimen, adding an Ad-HIVenv recombinant and envelope protein boost to test whether envelope antibodies would augment acute phase protection. Further, expecting cellular immunity to enhance chronic viremia control, we tested a multigenic group: Ad-HIVtat, -HIVenv, -SIVgag and -SIVnef recombinants and Tat, Env, and Nef proteins. All regimens were immunogenic. A hierarchy was observed in ELISPOT responses (Env gt Gag gt Nef gt Tat) and antibody titers (Env gt Tat gt Nef gt Gag). Following intravenous SHIV89.6P challenge, all macaques became infected. Compared to controls, no protection was seen in the Tat-only group, confirming previous reports. However, the multigenic group blunted acute viremia approximately 1 log (p = 0.017), and both the multigenic and tat/env groups reduced chronic viremia by 3 and 4 logs respectively compared to controls (multigenic, p = 0.0003; tat/env, p 0.0001). The strikingly greater reduction in the tat/env compared to the multigenic group (p = 0.014) was correlated with Tat and Env binding antibodies. As pre-challenge anti-Env antibodies lacked SHIV89.6P neutralizing activity, other functional anti-Env and anti-Tat activities are under investigation, as is a possible synergy between Tat and Env immunogens. We are continuing to monitor the remaining animals to assess possible survival differences between the groups.