MVA Prime/Novel Trimeric Cyclically Permuted Envelope Protein Boost Vaccines for HIV

本申请的总体目标是确定新的三聚抗体的免疫原性和保护功效。 gp 120抗HIV免疫原使用恒河猴模型。开发有效疫苗 在过去的三十年里，对抗HIV-1一直是一个难以实现的目标。RV 144疗效试验的结果 泰国首次在人类中证明了艾滋病毒感染可以通过接种疫苗来预防， 抗包膜（Env）抗体应答对这种保护有显著贡献。的主要关联 发现保护作用是对gp 120可变环V1 V2特异的非中和抗体， 最近的非人灵长类动物（NHP）试验支持了这一点，在这些试验中， 免疫缺陷病毒（SIV）感染也与抗V1 V2抗体相关。因此，我们假设艾滋病毒 除了中和抗体应答之外，还产生强烈和广泛的抗V1 V2应答的疫苗， 将显著提高对多种HIV-1分离株的保护。为此，我们最近描述了 新型三聚体gp 120免疫原CycP-gp 120的设计、免疫原性和功效。这种免疫原是 基于循环排列的gp 120，其中在V1环区域内产生从头N-末端 其中天然的N-和C-末端通过氨基酸接头链连接。为了诱导三聚体复合物， 将人软骨基质蛋白（hCMP）卷曲螺旋三聚化结构域与从头N-末端融合， 产生稳定的二硫键连接的三聚体GP 120。cycP-gp 120免疫豚鼠的研究 显示出对中和抗性（2级）HIV-1分离株的中和抗体的强烈诱导作用， 多个分支免疫家兔和恒河猴显示诱导高水平的高亲合力 HIV-1 Env特异性抗体具有显著的抗gp 70-V1 V2特异性应答，促进抗体 识别来自全球HIV-1分离株的多样化、多进化枝组的V1 V2序列。最近的研究， 恒河猴表明MVA初免/CycP加强方案可保护小鼠免受致病性SHIV感染 挑战在本研究中，我们将进一步优化CycP免疫原的设计和CycP的佐剂 蛋白加强，并测试CycP诱导的抗体应答的能力，以进一步增强对HIV的保护 在恒河猴中使用异源致病性2级SHIV攻击。

The overall goal of this application is to determine the immunogenicity and protective efficacy of novel trimeric gp120 immunogens against HIV using the rhesus macaque model. Development of an effective vaccine against HIV-1 has been an elusive goal for the past three decades. The results from the RV144 efficacy trial in Thailand provided a first proof in humans that HIV infection can be prevented by vaccination and demonstrated that anti-envelope (Env) antibody response contributes significantly for this protection. The major correlate of protection was found to be non-neutralizing antibodies specific for the variable loops V1V2 of gp120, a finding supported by recent non-human primate (NHP) trials in which protection from neutralization resistant simian immunodeficiency virus (SIV) infection also correlated with anti-V1V2 antibodies. Thus, we hypothesize HIV vaccines that generate a strong and broad anti-V1V2 response, in addition to neutralizing antibody response, will significantly improve protection against diverse HIV-1 isolates. Towards this, we recently described the design, immunogenicity and efficacy of a novel trimeric gp120 immunogen, CycP-gp120. This immunogen is based on a cyclically permuted gp120 in which a de novo N-terminus is generated within the V1 loop region with the native N- and C- termini joined via an amino acid linker chain. To induce a trimeric complex, the human cartilage matrix protein (hCMP) coiled-coil trimerization domain was fused to the de novo N-termini, resulting in a stabilized, disulfide bond linked trimeric gp120. Immunization of guinea pigs with cycP-gp120 showed strong induction of neutralizing antibodies against neutralization resistant (tier-2) HIV-1 isolates from multiple clades. Immunization of rabbits and rhesus macaques showed induction of high levels of high avidity HIV-1 Env specific antibodies with a remarkable anti-gp70-V1V2 specific response, promoting antibodies recognizing V1V2 sequences from a diverse, multi-clade panel of global HIV-1 isolates. More recent studies in rhesus macaque showed that MVA prime/CycP boost regimen confers protection against pathogenic SHIV challenges. In this proposal we will further optimize the CycP immunogen design and the adjuvant for CycP protein boost, and test the ability of CycP-induced antibody response to further enhance protection against HIV using a heterologous pathogenic tier 2 SHIV challenge in rhesus macaques.