Neonatal Immunity to novel TF SHIVs

摘要 一种能诱导广谱中和抗体(BNAbs)的HIV-1包膜(Env)疫苗仍然难以捉摸，在 部分原因是我们对自然感染过程中bNab诱导的机制了解有限。最近 开发的猴-人嵌合免疫缺陷病毒(SHIV)携带HIV-1传播的env- 与在HIV-1感染的成年人中诱导bNab相关的方正(TF)病毒现在提供了一种 建立bNab发育机制的实验模型。约50%的人出现HIV-1 Env bNAbs 慢性感染者成人感染3-5年以上，但感染HIV-1的婴幼儿较多 经常产生bNAb，而且比成年人更快。了解细胞和分子机制 婴儿bNab发育的研究将促进疫苗策略的设计，以诱导bNAb。在最近的一项研究中 HIV-1环境免疫后新生儿和成年猕猴免疫细胞的单细胞转录组图谱 研究发现，新生儿的边缘带(MZ)样B细胞的频率比成年人高。MZ B细胞 作为先天类淋巴细胞发挥作用，并对病原体产生快速抗体反应，但是否 新生儿主要利用MZ B细胞产生针对HIV-1感染的抗体，或者接种疫苗尚不清楚。在……里面 成人，bNab诱导的一个关键相关因素是卵泡辅助细胞(TFH)与调节细胞(TFR)CD4T细胞的比率 血液中的亚群，以及TFH细胞被认为刺激bNab B细胞在 生发中心(GC)。HIV-1感染婴儿的血液或淋巴组织中TFH是否升高 未知。在这笔赠款中，我们将使用血液和免疫组织来测试婴儿对新的TF环境的免疫力 SHIV，并确定引起NABS的B细胞亚群，包括bNAbs，以及CD4T细胞的作用 在婴幼儿NAB诱导中。这项建议的具体目标如下： 目的1.与成年猕猴比较，确定新生儿和成年猕猴病毒进化和免疫逃逸的动态 新城疫病毒感染 目的2.确定新生儿新城疫病毒感染的B细胞进化途径 目的3.询问淋巴结GC和外周血中CD4T、B细胞亚群，并评价其功能。 新生儿新城疫病毒感染

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