Project 2: Microbial determinants of HIV broadly-neutralizing antibody precursor induction in infants

摘要-项目2 在全球范围内，每年有60万年轻人感染HIV-1。因此，迫切需要 制定早期生命疫苗战略，保护年轻人免受艾滋病毒感染。这种早期疫苗应该 引发保护性广泛中和抗体（bNAbs），这些抗体已被证明可有效对抗感染 在非人类灵长类动物和人类身上。新的，合理设计的天然样HIV包膜三聚体疫苗 已经开发了接合生殖系B细胞受体并驱动bNAb进化的基因。这些B细胞谱系- 在50-60%的婴儿和成年非人灵长类动物中，基础疫苗诱导bNAb前体， 试验数据表明，一些人也会产生bNAb。虽然这些发现提供了重要的承诺， 尽管研制有效的艾滋病毒疫苗的长期目标即将实现，但我们对艾滋病毒的认识仍存在差距。 bNAb诱导的决定因素，导致只有一半的疫苗接种者产生有利的反应。现在 很明显，微生物组与免疫系统的发育和调节错综复杂地交织在一起， 这些微生物群-免疫相互作用对疫苗应答至关重要。我们的初步数据证实 微生物组是影响疫苗反应的必要和可改变的因素， 细菌分类群与用基于HIV Env的疫苗免疫产生的抗体滴度正相关。 因此，项目2建议定义可以作为内源性佐剂利用的特定微生物特征 与项目1确定的最佳外源性佐剂一起帮助诱导HIV bNAb 在用BG 505 GT1.1 SOSIP三聚体免疫原接种后，具体而言，本项目的目标1 将结合鸟枪宏基因组数据和微生物-表型三角测量，这是一种新的微生物组发现 我们开发的平台，以定义与HIV bNAb前体诱导相关的微生物特征。 目标2将检验一些肠道细菌倾向于有益的疫苗反应的假设 通过帮助诱导疫苗引发的抗体，这些抗体与微生物组交叉反应。增强 我们的工作的翻译潜力，我们将检查两个婴儿NHP中的微生物组交叉反应抗体 还有人类最后，Aim 3将开发出一种特定生物人类B细胞谱系基因敲入小鼠模型， 通过实验确定微生物组在bNAb前体诱导中的作用，包括功能验证 生物信息学鉴定的微生物特征。总之，本项目的结果将阐明具体的 调节免疫景观的微生物，使得更大百分比的基于B细胞谱系的疫苗 接受者产生bNAb前体。最终，这些类似杀虫剂的微生物可以被整合到未来的 疫苗战略。

Abstract – Project 2 Globally, 600,000 young adults become infected with HIV-1 each year. Therefore, there is an urgent need to develop an early life vaccine strategy that protects young adults from HIV infection. This early life vaccine should elicit protective broadly neutralizing antibodies (bNAbs), which have been shown to be effective against infection in nonhuman primates and humans. Newer, rationally designed native-like HIV envelope trimer-based vaccines that engage germline B cell receptors and drive evolution of bNAbs have been developed. These B cell lineage- based vaccines induce bNAb precursors in 50–60% of infant and adult nonhuman primates, and early clinical trial data suggests some humans also develop bNAbs. While these findings offer significant promise that the long-standing goal of an effective HIV vaccine is on the horizon, there is a gap in our understanding of the determinants of bNAb induction that results in only half of vaccinees developing a favorable response. It is now clear that the microbiome is intricately intertwined with the development and modulation of the immune system, and that these microbiome–immune interactions are critical for vaccine responses. Our preliminary data confirm that the microbiome is a necessary and modifiable factor that influences vaccine responses, with specific bacterial taxa positively associated with antibody titers resulting from immunization with HIV Env-based vaccines. Thus, Project 2 proposes to define specific microbial features that can be harnessed as an endogenous adjuvant to help—along with optimal exogenous adjuvants identified by Project 1—drive induction of HIV bNAb precursors after vaccination with the BG505 GT1.1 SOSIP trimer immunogen. Specifically, Aim 1 of this project will couple shotgun metagenomic data and microbe–phenotype triangulation, a novel microbiome discovery platform we developed, to define microbial features that associate with the induction of HIV bNAb precursors. Aim 2 will test the hypothesis that some commensal bacteria predispose towards beneficial vaccine responses by helping induce vaccine-elicited antibodies that are cross-reactive with the microbiome. To enhance the translational potential of our work, we will examine microbiome cross-reactive antibodies in both infant NHPs and humans. Finally, Aim 3 will develop a gnotobiotic human B cell lineage knock-in mouse model to experimentally define the role of the microbiome in bNAb precursor induction, including functionally validating the bioinformatically identified microbial features. Taken together, the results of this Project will elucidate specific microbes that modulate the immune landscape such that a greater percentage of B cell lineage-based vaccine recipients develop bNAb precursors. Ultimately, these adjuvant-like microbes can be incorporated into future vaccine strategies.