Neonatal Immunity to novel TF SHIVs

摘要 一种激发广泛中和抗体（bnAb）的HIV-1包膜（Env）疫苗仍然难以捉摸， 部分原因是我们对自然感染过程中bnAb诱导机制的了解有限。最近 开发了携带HIV-1传播的Env的猴-人嵌合免疫缺陷病毒（SHIV）， 在HIV-1感染的成年个体中与bnAb诱导相关的创始者（TF）病毒现在提供了一种新的治疗方法。 实验模型，以建立bnAb发展的机制。HIV-1 Env bnAb在约50%的 慢性感染者成人在3-5年内感染，但HIV-1感染的婴儿和儿童更多 他们经常会产生bnAb，而且比成年人更快。了解细胞和分子机制 婴儿bnAb开发的快速发展将促进疫苗策略的设计以引发bnAb。在最近的一项关于 在HIV-1 Env疫苗接种后新生和成年猕猴免疫细胞的单细胞转录组谱，我们 发现与成人相比，新生儿具有更高频率的边缘区（MZ）样B细胞。MZ B细胞 已知其功能类似于先天性淋巴细胞，并对病原体产生快速的抗体反应，但是否 新生儿主要利用MZ B细胞来产生抗HIV-1感染的Ab，或者疫苗接种是未知的。在 在成年人中，bnAb诱导的关键相关性是滤泡辅助性（Tfh）与调节性（Tfr）CD 4 T细胞的比率 假定Tfh细胞刺激bnAb B细胞获得亲和力成熟， 老年中心（GC）。HIV-1感染婴儿的血液或淋巴结中Tfh是否升高， 未知在这项资助中，我们将使用血液和免疫组织来询问婴儿对新TF Env SHIV，并确定产生NAb的B细胞亚群，包括bnAb，以及CD 4 T细胞的作用 在婴儿NAb诱导中。这项建议的具体目标如下： 目标1.确定新生猕猴与成年猕猴中病毒进化和免疫逃逸的动态 SHIV感染 目标2.定义新生儿SHIV感染引起的B细胞进化途径 目标3。探讨淋巴结GC和血CD 4 T、B细胞亚群，并评价其在淋巴结转移中的作用。 新生儿SHIV感染

Abstract A HIV-1 Envelope (Env) vaccine that elicits broadly neutralizing antibodies (bnAbs) has remained elusive, in part due to our limited understanding of the mechanisms of bnAb induction during natural infection. Recently developed simian-human chimeric immunodeficiency viruses (SHIVs) bearing Envs from HIV-1 transmitted- founder (TF) viruses associated with bnAb induction in HIV-1 infected adult individuals now provide an experimental model to establish the mechanisms of bnAb development. HIV-1 Env bnAbs develop in ~50% of chronically-infected adults in over 3-5 years of infection, but HIV-1-infected infants and children more frequently develop bnAbs and do so faster than adults. Understanding the cellular and molecular mechanisms of infant bnAb development will facilitate design of vaccine strategies to elicit bnAbs. In a recent study of the single cell transcriptome profile of neonate and adult macaque immune cells after HIV-1 Env vaccination, we found that neonates had a higher frequency of marginal zone (MZ)-like B cells compared to adults. MZ B cells are known to function as innate-like lymphocytes and mount a rapid Ab response to pathogens, but whether neonates predominantly utilize MZ B cells to generate Abs to HIV-1 infection or vaccination is not known. In adults, a key correlate of bnAb induction is the ratio of follicular helper (Tfh) to regulatory (Tfr) CD4 T cell subsets in blood, and Tfh cells are postulated to stimulate bnAb B cells to acquire affinity maturation in germinal centers (GC). Whether Tfh are elevated in blood or lymph nodes of HIV-1-infected infants is unknown. In this grant, we will use blood and immune tissues to interrogate infant immunity to new TF Env SHIVs, and determine the B cell subsets that give rise to NAbs, including bnAbs, and the roles of CD4 T cells in infant NAb induction. The specific aims for this proposal are as follows: Aim 1. Determine the dynamics of virus evolution and immune escape in neonatal compared to adult macaque SHIV infections Aim 2. Define B cell evolution pathways elicited in neonatal SHIV infections Aim 3. Interrogate lymph node GC and blood CD4 T and B cell subsets, and evaluate their function in neonatal SHIV infections