Determinants of HIV broadly-neutralizing antibody precursor induction in infants

摘要--总体 诱导针对HIV包膜糖蛋白(Env)的广谱中和抗体 被认为对有效的艾滋病毒疫苗至关重要。使用针对天然环境的三聚体进行合理的疫苗设计 各自的生殖系B细胞受体已经演变为最有希望的策略。然而，到目前为止，bNAb前体 接种者的产量还没有超过50%。该计划的目标是确定早期决定因素 BNab前体诱导，重点放在佐剂和宿主微生物群的作用上，利用广泛和整合的 组学方法破译与bNAb发育相关的机制。在艾滋病毒感染中，血浆 BNAbs在少数成年人中出现，并且只在几年后出现，而携带艾滋病毒的婴儿中的bNAbs可能是 最早在感染后一年即可检测到。有趣的是，从婴儿身上分离出的bNAb似乎需要的更少。 体细胞超突变达到与成人的bNAbs相似的广度，意味着潜在的不同机制 BNAb的发展。我们提供了婴儿恒河猴(RM)免疫的初步数据 BG505种系靶向(GT)1.1 SOSIP三聚体与TLR7.8，8佐剂3M-052佐剂一起导致 在5只动物中有3只诱导了类似VRC01的CD4结合位点bNAb前体，其频率与 成人右室(6例/12例)。婴儿红斑狼疮的血浆抗体也针对更广泛的表位。 与成年的Rm相比，显示出更大的多反应性。尽管进行了额外的免疫接种，剩下的2人 婴儿rm没有发展出这种中和特征，这表明早期事件在驱动bNAb方面是关键的。 发展。在婴儿中，早期免疫部分是由进化中的微生物群决定的。许多生物的多反应性， 虽然不是全部，但bNAbs进一步支持了微生物区系在bNAb发展中的潜在作用，我们假设 可以利用婴儿免疫系统和微生物区系的动态来优化诱导 HIV疫苗产生的bNAbs。利用婴儿BG505 GT1.1 SOSIP疫苗模型和应用系统 生物学方法，我们将确定bNAb诱导的发育途径是如何改变的 不同佐剂(项目1)、微生物组(项目2)和 宿主免疫和微生物区系之间的相互作用(生物统计和计算分析[BCA]核心)。 这些项目将得到非人灵长类动物(NHP)和B细胞核心的支持，并有组织和 行政核心的财政支持。在目标1和目标2中，我们将定义早期免疫的差异 对BG505产生或不产生bNAbs的接种者之间的反应和分子签名 GT1.1通过佐剂(项目1)和微生物区系(项目2)调整疫苗主成分进行SOSIP疫苗接种。 AIM 3将开发集成免疫、微生物组和分子签名的建模方法来预测 BNab前体的发展。该计划的结果将确定归纳过程中的关键决定因素 BNAb前体的数量。在未来的研究中，我们将调整这些因素，以优化艾滋病毒疫苗策略。这个 新开发的计算模型将有助于对bNAb开发潜力的疫苗筛选。

ABSTRACT – OVERALL The induction of broadly neutralizing antibodies (bNAbs) against the HIV envelope glycoprotein (Env) is considered vital for an effective HIV vaccine. Rational vaccine design applying native Env-like trimers that target the respective germline B cell receptor have evolved as the most promising strategy. Yet, so far, bNAb precursor yields have not exceeded 50% of vaccinees. The goal of this Program aims to identify early determinants of bNAb precursor induction, with a focus on the role of adjuvants and host microbiota, utilizing broad and integrated omics approaches to decipher the mechanisms associated with bNAb development. In HIV infection, plasma bNAbs develop in a minority of adults and only after several years, whereas bNAbs in infants with HIV can be detected as early as one year post infection. Interestingly, bNAbs isolated from infants appear to require less somatic hypermutations to achieve similar breadth as bNAbs of adults, implying potentially different mechanisms of bNAb development. We present preliminary data that immunization of infant rhesus macaques (RM) with BG505 germline-targeting (GT)1.1 SOSIP trimers adjuvanted with the TLR7,8 adjuvant 3M-052 resulted in the induction of VRC01-like CD4 binding site bNAb precursors in 3 of 5 animals, a frequency comparable to that observed in adult RM (6 of 12). Plasma antibodies of infant RM also targeted a broader array of epitopes compared to adult RM, indicative of greater polyreactivity. Despite additional immunizations, the remaining 2 infant RM did not develop this neutralization signature, suggesting that early events are critical in driving bNAb development. In infants, early immunity is partially defined by the evolving microbiota. The polyreactivity of many, although not all, bNAbs, further supports a potential role of microbiota in bNAb development We hypothesize that the dynamic state of the infant immune system and microbiota can be exploited to optimize the induction of bNAbs by HIV vaccines. Leveraging the infant BG505 GT1.1 SOSIP vaccine model and applying systems biology approaches, we will identify how the developmental pathways of bNAb induction are altered by the modulation of the vaccine prime by different adjuvants (Project 1), the microbiome (Project 2), and the interactions between host immunity and microbiota (Biostatistics and Computational Analysis [BCA] Core). The Projects will be supported by the Nonhuman Primate (NHP) and the B Cell Cores, with organizational and fiscal support by the Administrative Core. In Aims 1 and 2, we will define differences in early immune responses and molecular signatures between vaccinees who do or do not develop bNAbs in response to BG505 GT1.1 SOSIP vaccination by modulating the vaccine prime via adjuvants (Project 1) and microbiota (Project 2). Aim 3 will develop modeling approaches that integrate immune, microbiome, and molecular signatures to predict the development of bnAb precursors. The results of the Program will identify critical determinants in the induction of bNAb precursors. In future studies, we will modulate these factors to optimize HIV vaccine strategies. The newly developed computational models will facilitate vaccine screening for the potential of bNAb development.