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

总结 尽管进行了数十年的HIV-1疫苗研究，但没有免疫原或候选疫苗的例子， 一致地引发有效的广泛中和抗体（bNAb）。大多数bNAb的例子来自天然的 HIV-1感染的人类，但即使这样，他们只发展后，几年的感染，并在只有一个 个体的子集。尽管如此，人类有潜力制造有效的bNAb的发现， 刺激了深入的研究，以确定这些抗体的靶表位及其发展途径 从未突变的生殖系B细胞受体（BCR）到成熟bNA B。最近，研究集中在 bNAb和HIV-1 Env序列的共同进化途径，引发它们，希望推断出特定的 Env序列可以发展成免疫原，其接合并刺激生殖系和中间体 祖先BCR。这一策略已被研究人员所倡导，他们追求“B细胞谱系设计”和“细胞分化”。 “反向疫苗学”方法来开发疫苗。我们建议理性艾滋病的一个主要障碍- 1疫苗设计的缺点是缺乏动物模型，在该动物模型中，可以以一致的免疫应答实现bNAb的诱导。 和可重复的方式，使得负责bNAb诱导的分子事件可以被破译 并用于指导反复的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--由SHIV生物学、病毒-抗体协同进化、 和B谱系疫苗设计-以克服这一关键的障碍。我们假设：（i）原发性HIV-1 Env 糖蛋白，如果以其天然构象作为持续复制的SHIV向远系繁殖， 不同的恒河猴（RM），将导致一致的病毒-抗体协同进化模式，重演那些 在感染携带同源Env的HIV-1毒株的人中观察到的模式;（ii）含有 在人类中引发bNab的原代HIV-1 Env将结合直系生殖系和中间祖先 RM中的BCR，并导致产生自体和异源2级中和抗体;以及 (iii)通过鉴定进化以实现中和广度的RM种系和中间祖先BCR， 连同它们的同源SHIV Env免疫原（“免疫型”），我们将首次掌握一种 一个可重复的实验系统，在其中迭代设计，测试和指导新的 基于B谱系设计和反向疫苗学平台的候选疫苗。为了验证这个假设， 我们提出了三个高度相关的研究项目和三个核心：项目1 -环境进化和 SHIV感染恒河猴和HIV-1感染人的中和抗体产生 项目2 -SHIV中中和B细胞反应的群体动力学- 感染的猕猴（Kelsoe）;项目3 -来自SHIV的HIV连续包膜的免疫原设计- 被感染的猕猴（Haynes）。这些项目将通过核心A -行政（Shaw）实现;核心B -病毒式 和Antibody Gene Sequencing（Hahn）;和Core C-Bioinformatics and Statistics（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).