SHIV/HIV Env-Antibody Coevolution as a Guide to Iterative Vaccine Design

摘要 尽管对HIV-1疫苗进行了数十年的研究，但还没有免疫原或候选疫苗的例子 持续诱导有效的广谱中和抗体(BNAbs)。大多数bNAbs的例子来自天然 人类感染HIV-1，但即便如此，它们也只是在感染几年后才发展起来，而且只在 个体的子集。尽管如此，人类有潜力制造有效的bNAbs这一发现 刺激了密集的研究，以确定这些抗体的目标表位及其发育途径 从未突变的生殖系B细胞受体(BCR)到成熟的bNAb。最近，研究的重点是 BNAbs和HIV-1 env序列的共同进化途径，希望通过它们来推断特定的 可发展为免疫原的环境序列，可参与并刺激生殖系和中间体 祖先BCR。这一策略一直受到研究人员的拥护，他们既研究了B细胞谱系设计，也研究了 疫苗开发的“反向疫苗学”方法。我们认为，理性艾滋病毒的一个主要障碍-- 1疫苗设计缺乏一种动物模型，在这种动物模型中可以一致地实现对bNAbs的诱导 以及可重现的方式，使得可以破译引起bNAb诱导的分子事件 并用于指导迭代HIV-1疫苗设计。这个HIVRAD应用程序提出了一个新的假设， 一项综合研究计划--得到希沃克病毒生物学、病毒抗体共同进化、 和B血统疫苗设计--克服这一关键障碍。我们假设：(I)主要的HIV-1环境 糖蛋白，如果以其天然构象存在，作为持续复制的Shiv，以遗传方式繁殖 不同的恒河猴(RMS)，将导致一致的病毒-抗体共同进化模式，概括这些 在感染带有同源env的HIV-1毒株的人身上观察到的模式；(Ii)含有 人类感染的HIV-1原发毒株将与同源生殖系和中间祖先结合。 RMS中的BCR，并导致产生自体和异源的第二层中和抗体；以及 (Iii)通过鉴定进化到中和广度的RM种系和中间祖先BCR， 连同它们的同源新城疫病毒环境免疫原(“免疫类型”)，我们将首次拥有 可重复的实验系统，用于迭代设计、测试和指导小说的开发 基于B系设计和反向疫苗接种平台的候选疫苗。为了检验这一假设， 我们提出了三个高度相关的研究项目和三个核心：项目1-环境演变和 新城疫病毒感染恒河猴和人类感染HIV-1毒株的中和抗体激发 承载同源环境(Shaw)；项目2-SHIV中和B细胞反应的群体动力学 受感染猕猴(Kelsoe)；项目3-来自SHIV的HIV序列信封的免疫原设计- 受感染的猕猴(海恩斯)。这些项目将由核心A支持-行政(Shaw)；核心B-病毒 和抗体基因测序(HAHN)；以及核心C-生物信息学和统计学(Korber)。

SUMMARY Despite decades of HIV-1 vaccine research, there are no examples of immunogens or candidate vaccines that consistently elicit potent broadly neutralizing antibodies (bNAbs). Most examples of bNAbs come from natural HIV-1 infection of humans, but even then, they develop only after several years of infection and in only a subset of individuals. Nonetheless, the finding that humans have the potential to make potent bNAbs has spurred intensive research to identify the target epitopes of these antibodies and their developmental pathways from unmutated germline B cell receptor (BCR) to mature bNAb. Recently, research has focused on the coevolutionary pathways of bNAbs and HIV-1 Env sequences that elicit them in hopes of inferring particular Env sequences that can be developed into immunogens that engage and stimulate germline and intermediate ancestor BCRs. This strategy has been championed by investigators pursuing both “B cell lineage design” and “reverse vaccinology” approaches to vaccine development. We propose that a major roadblock to rational HIV- 1 vaccine design is the lack of an animal model where the induction of bNAbs can be achieved in a consistent and reproducible manner such that the molecular events responsible for bNAb elicitation can be deciphered and used to guide iterative HIV-1 vaccine design. This HIVRAD application proposes a novel hypothesis and an integrated research plan – supported by promising new discoveries in SHIV biology, virus-Ab coevolution, and B lineage vaccine design – to overcome this critical roadblock. We hypothesize that: (i) primary HIV-1 Env glycoproteins, if presented in their native conformation as persistently replicating SHIVs to outbred, genetically diverse rhesus macaques (RMs), will lead to consistent patterns of virus-Ab coevolution that recapitulate those patterns observed in humans infected by HIV-1 strains bearing homologous Envs; (ii) SHIVs containing primary HIV-1 Envs that in humans elicited bNabs, will bind orthologous germline and intermediate ancestor BCRs in RMs, and lead to the development of autologous and heterologous tier 2 neutralizing antibodies; and (iii) by identifying RM germline and intermediate ancestor BCRs that evolve to achieve neutralization breadth, together with their cognate SHIV Env immunogens (“immunotypes”), we will have in hand for the first time a reproducible experimental system in which to iteratively design, test and guide the development of novel vaccine candidates based on both B lineage design and reverse vaccinology platforms. To test this hypothesis, we propose three highly inter-related research projects and three cores: Project 1 - Env Evolution and Neutralizing Antibody Elicitation in SHIV Infected Rhesus Macaques and in Humans Infected by HIV-1 Strains bearing Homologous Envs (Shaw); Project 2 - Population Dynamics of Neutralizing B-Cell Responses in SHIV- infected Macaques (Kelsoe); Project 3 - Immunogen Design of HIV Sequential Envelopes Derived from SHIV- infected Macaques (Haynes). These projects will be enabled by Core A - Administrative (Shaw); Core B - Viral and Antibody Gene Sequencing (Hahn); and Core C - Bioinformatics and Statistics (Korber).