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

胃肠道微生物组对宿主对效应记忆 T 细胞艾滋病疫苗和多次低剂量攻击反应的影响

• 批准号: 8992226
• 负责人: Xinxia Peng
• 金额: $ 21.75万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8992226
• 关键词: AIDS Vaccines; Acquired Immunodeficiency Syndrome; Affect; Animals; Blood specimen; CD8B1 gene; Cells; Communities; Computer software; Confounding Factors (Epidemiology); Cytomegalovirus; Data; Data Set; Databases; Diet; Disease; Dose; Dose-Limiting; Environmental Risk Factor; Exclusion; Exhibits; Foundations; Fred Hutchinson Cancer Research Center; Funding; Future; Gastrointestinal tract structure; Gene Expression; Generations; Genes; Goals; Head; Health; Health Sciences; Human; Immune; Immune response; Immunologic Deficiency Syndromes; Individual; Infection; Joints; Laboratories; Lead; Life; Life Style; Location; Macaca mulatta; Machine Learning; Mediating; Memory; Metagenomics; Microbiology; Modeling; Molecular Profiling; Monkeys; National Institute of Allergy and Infectious Disease; Network-based; Oregon; Pattern; Performance; Plasma; Process; Research; Research Project Grants; Role; SIV; Sampling; Scientist; Site; Swab; T cell response; T memory cell; Testing; Time; Universities; Vaccinated; Vaccination; Vaccine Research; Vaccines; Variant; Viral; Viral Proteins; Viremia; Virus; Virus Diseases; Washington; Whole Blood; base; design; efficacy testing; functional genomics; gastrointestinal; improved; microbiome; nonhuman primate; professor; public health relevance; rectal; response; vaccination strategy; vaccine development; vaccine effectiveness; vaccine efficacy; vaccine response; vaccine trial; vaccine-induced immunity; vector

 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.

 描述（由申请人提供）：该计算研究项目将分析来自大规模恒河猴艾滋病疫苗研究的胃肠道微生物组，宿主细胞免疫反应和宿主转录反应数据集。疫苗研究包括70只动物，分为5组，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）载体的效力。在以前的研究中，RhCMV/SIV疫苗引起了强大的效应记忆T细胞应答。在用高致病性SIVmac 239攻击后，约50%的RhCMV/SIV疫苗接种的猴表现出病毒控制模式，其特征在于病毒血症的“短暂”，随后将血浆病毒血症控制到不可检测的水平。1 ~ 3年后，RhCMV/SIV保护的猴子没有SIV感染的迹象，这表明免疫介导的病毒清除。造成这50%疗效的机制尚不清楚，但可能反映了SIV进入位点或早期复制位点的T细胞应答。该项目将研究胃肠道微生物组对RhCMV/SIV诱导的效应记忆T细胞应答和对SIVmac 239攻击的保护作用。该项目包括两个基于计算的特定目标：1）定义接种疫苗前后以及重复限制剂量SIVmac 239挑战期间肠道微生物组的组成; 2）确定肠道微生物组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，16 S核糖体序列数据（从直肠拭子中获得）将用于确定操作分类单位。将使用Mothur和Qiime宏基因组软件确定细菌种类随时间的变化和个体动物内的变化。 将使用非参数统计分析以及共现和共排除网络来鉴定与重复限制剂量直肠内SIVmac 239激发后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CD 4+和CD 8 + T细胞应答之间的关联。基于基因模块和基于相关网络的方法将用于确定微生物组组成与宿主转录反应（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组-宿主相互作用及其在引发保护性疫苗衍生的效应记忆T细胞反应中的作用。这种理解将为未来的疫苗接种策略提供信息，并试图调节微生物组组成以影响疫苗效力。