Neutralizing and non-neutralizing antibody effector functions in HIV infected children

摘要 2016年，估计有61万名15至24岁的年轻人新感染 感染了艾滋病毒预防青少年艾滋病毒感染可能需要在儿童时期接种疫苗， 以在初次性行为之前获得保护性免疫。由于成年和早期生活的差异 免疫系统，了解儿童艾滋病毒特异性抗体反应的发展至关重要， 指导在儿科人群中实施艾滋病毒疫苗。以前的研究调查艾滋病毒 儿童中的功能性抗体大小有限，但他们的结果表明潜在的重要差异 成人和儿童之间的关系。值得注意的是，1）儿童可能会更早地发展中和宽度 2）儿童血浆中和宽度可能由多克隆抗体介导， 成人，其中一种或两种抗体特异性负责广度;和3）婴儿广泛 中和抗体（bnAb）与成人bnAb相比可能具有较低水平的体细胞超突变。 由于这些先前研究的小样本量限制了他们发现的推广，我们 从已完成的儿科队列研究中获得了大量ART初治HIV感染儿童的样本 研究生命早期HIV特异性抗体反应的发展。初步实验使用 这些样本表明，总体而言，1至3岁的儿童具有明显更大的中和宽度 这表明在儿童中诱导广泛中和比在成人中更容易。 重要的是，通过疫苗接种在儿童中引起广泛中和需要存在一个池 具有开发bnAb（bnAb前体）潜力的B细胞。然而，尽管最近的研究表明， bnAb前体可以在健康成人中以低频率检测到， 孩子目前未知。这项研究的总体目标是评估艾滋病毒特异性 幼儿的抗体反应。我们主要关注bnAb反应，但因为1）最近的研究 已经表明Fc效应子功能是成人中和宽度的预测因子，2）非- 中和反应与临床前研究中的保护作用有关， RV 144疫苗试验中观察到的部分保护作用;我们还将测量非中和功能 抗体反应。我们假设生命早期的免疫景观呈现出激发的优势 保护性HIV特异性抗体对成人免疫系统的作用。我们的具体目标是：1）量化和 在一个大的HIV感染儿童队列中描述HIV中和宽度; 2）：评估 HIV感染儿童的多功能抗体应答与中和广度发展之间的关系; 最后3）量化未感染HIV的儿童中潜在bnAb前体的频率。本研究将 提高目前对艾滋病毒bnAb和儿童非中和抗体发展的认识， 确定在生命早期开始免疫接种是否有利于引发保护性抗体应答

Abstract In 2016, it was estimated that 610,000 young people between the ages of 15 to 24 years were newly infected with HIV. Preventing adolescent HIV infections will likely require the administration of a vaccine in childhood in order to achieve protective immunity prior to sexual debut. Because of differences in the adult and early life immune systems, understanding the development of HIV-specific antibody responses in children is critical to guide the implementation of an HIV vaccine in pediatric populations. Previous studies investigating HIV functional antibodies in children were limited in size, but their results suggested potential important differences between adults and children. It was notably reported that 1) children may develop neutralization breadth earlier than adults; 2) plasma neutralization breadth in children may be mediated by polyclonal antibodies in contrast to adults in which one or two antibody specificities are responsible for breadth; and 3) infant broadly neutralizing antibodies (bnAbs) may have lower levels of somatic hypermutation as compared to adult bnAbs. Because the small sample size of these previous studies limits the generalization of their findings, we have obtained a large panel of samples of ART naïve HIV-infected children from completed pediatric cohort studies to investigate the development of HIV-specific antibody responses in early life. Preliminary experiments using these specimens indicated that overall, 1 to 3-year-old children have significantly more neutralization breadth than adults, suggesting that it could be easier to induce broad neutralization in children than in adults. Importantly, elicitation of broad neutralization in children through vaccination will require the existence of a pool of B cells with the potential to develop bnAbs (bnAb precursors). Yet, while recent studies have demonstrated that bnAb precursors can be detected at low frequency in healthy adults, the frequency of bnAb precursors in children is currently unknown. The overall goal of this study is to assess the development of HIV-specific antibody responses in young children. Our primary focus in on bnAb responses, but because 1) Recent studies have indicated that Fc effector functions are predictors of neutralization breadth in adults and 2) non- neutralizing responses have be associated with protection in preclinical studies and might have contributed to the partial protection observed in the RV144 vaccine trial; we will also measure non-neutralizing functional antibody responses. We hypothesize that the early life immune landscape presents advantages for elicitation of protective HIV-specific antibodies over the adult immune system. Our specific aims are: 1) To quantify and characterize HIV neutralization breadth in a large cohort of HIV-infected children; 2): To assess the association between polyfunctional Ab responses and neutralization breadth development in HIV infected children; and finally 3) To quantify the frequency of potential bnAb precursors in HIV uninfected children. This study will increase current understanding of HIV bnAb and non-neutralizing antibody development in children and help determine if initiating immunization in early life is advantageous for elicitation of protective antibody responses