Impact of Gastrointestinal Microbiome on the Host Response to an Effector-Memory T-Cell AIDS Vaccine and Multiple Low-Dose Challenge

 描述(申请人提供)：这个计算研究项目将分析胃肠道微生物组、宿主细胞免疫反应和宿主转录反应数据集，这些数据集来自于一项大规模的恒河猴艾滋病疫苗研究。疫苗研究包括分成五组的70只动物，旨在测试表达主要猴免疫缺陷病毒(SIV)蛋白的巨细胞病毒(CMV)载体的有效性。在以前的研究中，RhCMV/SIV疫苗可以激发强大的效应-记忆T细胞反应。在用高致病性SIVmac239攻击后，大约50%接种了RhCMV/SIV疫苗的猴子表现出一种病毒控制模式，其特征是病毒血症的“短暂”，随后血浆病毒血症控制到无法检测到的水平。一到三年后，受RhCMV/SIV保护的猴子没有表现出SIV感染的迹象，这表明病毒通过免疫媒介清除。导致50%有效率的机制尚不清楚，但可能反映了SIV进入部位或早期复制部位的T细胞反应。该项目将研究胃肠道微生物组在RhCMV/SIV诱导的效应记忆T细胞反应中的作用以及对SIVmac239攻击的保护作用。该项目包括两个基于计算的特定目标：1)确定接种疫苗前后和重复限制剂量SIVmac239挑战期间肠道微生物群的组成；2)确定肠道微生物群的组成如何与保护性免疫细胞反应和疫苗诱导的宿主转录反应相关。在目标1中，将使用16S核糖体序列数据(从直肠拭子获得)来确定可操作的分类单位。使用Mothur和Kiime元基因组软件将确定细菌种类随时间和个体动物内的变化。非参数统计分析以及共生和共排除网络将用于识别在反复限制剂量直肠内SIVmac239挑战后与SIV感染的进展或控制相关的细菌种类。在目标2中，将使用主成分分析来确定微生物组组成与SIV特异性的CD4+和CD8+T细胞反应之间的关联。基于基因模块和相关网络的方法将被用来确定微生物组组成和宿主转录反应(从全血样本中收集)之间的关联。总之，这些分析将使我们能够更好地了解微生物群与宿主的相互作用及其在诱导保护性疫苗衍生的效应器-记忆T细胞反应中的作用。这种理解将为未来的疫苗接种战略和调节微生物群组成以影响疫苗效力的尝试提供信息。

 DESCRIPTION (provided by applicant): This computational research project will analyze gastrointestinal microbiome, host cellular immune response, and host transcriptional response datasets derived from a large-scale rhesus macaque AIDS vaccine study. The vaccine study includes 70 animals divided into five groups and is designed to test the efficacy of a cytomegalovirus (CMV) vector expressing the major simian immunodeficiency virus (SIV) proteins. In previous studies, RhCMV/SIV vaccines elicit a robust effector-memory T cell response. After challenge with highly pathogenic SIVmac239, approximately 50% of RhCMV/SIV-vaccinated monkeys exhibit a pattern of viral control that is characterized by a "blip" of viremia followed by control of plasma viremia to undetectable levels. One to three years later, RhCMV/SIV-protected monkeys show no sign of SIV infection, suggesting immune-mediated clearance of the virus. The mechanisms responsible for this 50% efficacy are not clear, but may reflect T cell responses at the site of SIV entry or sites of early replication. Thi project will investigate the role of the gastrointestinal microbiome on RhCMV/SIV-induced effector-memory T cell responses and protection against SIVmac239 challenge. The project includes two computationally based Specific Aims: 1) Define the composition of the gut microbiome prior to and after vaccination and during repeated limiting-dose SIVmac239 challenge; and 2) Determine how the composition of the gut microbiome correlates with protective immune cell responses and vaccine-induced host transcriptional responses. In Aim 1, 16S ribosomal sequence data (obtained from rectal swabs) will be used to determine operational taxonomic units. Variation in bacterial species over time and within individual animals will be determined using Mothur and Qiime metagenomic software. Nonparametric statistical analyses and co-occurrence and co-exclusion networks will be used to identify bacterial species associated with progression or control of SIV infection after repeated limiting-dose intrarectal SIVmac239 challenge. In Aim 2, principle component analysis will be used to identify associations between microbiome composition and SIV-specific CD4+ and CD8+ T cell responses. Gene module-based and correlation network-based approaches will be used to determine associations between microbiome composition and host transcriptional responses (collected from whole blood samples). Together, these analyses will allow us to better understand microbiome-host interactions and their role in eliciting a protective vaccine-derived effector-memory T cell response. Such understanding will inform future vaccination strategies and attempts to modulate microbiome composition to affect vaccine efficacy.