Understanding Unconventional CD8+ T cell Responses in Protection from HIV

了解非常规 CD8 T 细胞反应在预防 HIV 方面的作用

• 批准号: 9623141
• 负责人: Scott G Hansen
• 金额: $ 84.72万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9623141
• 关键词: Alleles; Animals; Antigens; Bioinformatics; Blood specimen; CD8-Positive T-Lymphocytes; CD8B1 gene; Cellular Immunity; Clinic; Complex; Cytomegalovirus; Cytoprotection; Development; Dose; Dose-Limiting; Effectiveness; Endothelial Cells; Event; Exhibits; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; HIV; HIV vaccine; HIV-1; Health Priorities; Human; Immune; Immune response; Immunity; Immunogenetics; Immunologics; Individual; Infection; Macaca; Macaca mulatta; Maps; Measures; Mediating; MicroRNAs; Modeling; Monitor; Pathogenicity; Phase; Plasma; Plasma Cells; Population; Positioning Attribute; Property; RNA; Recording of previous events; Research; Role; SIV; SIV Vaccines; Sexual Transmission; Site; T cell response; Tissues; Translations; Vaccinated; Vaccines; Variant; Viral Load result; Viremia; Whole Blood; base; cell type; clinical translation; global health; immunoregulation; improved; mRNA sequencing; nonhuman primate; novel vaccines; pre-clinical; prevent; prophylactic; repaired; response; transcriptomics; vector; vector vaccine

Project Summary With 36 million people currently living with HIV worldwide, developing a prophylactic HIV vaccine that protects against sexual transmission remains a top global health priority. A pre-clinical HIV vaccine approach based on strain 68-1 of rhesus cytomegalovirus expressing SIV antigens (RhCMV/SIV) elicits cellular unique unconventionally MHC-restricted T cell responses that are able to stringently control and ultimately clear pathogenic SIV replication in ~50% of vaccinated rhesus macaques (RM). However, it remains unknown if the 68-1 RhCMV-induced unique immunity and protection from SIV is a RM-specific phenomenon. To investigate this question as a means to successfully translation RhCMV into the clinic as an HIV vaccine, we will recapitulate these results using a Mauritian cynomolgus macaques (MCM), a nonhuman primate species with unique MHC genetics that reflect human immunogenetics. In specific aim 1, we will characterize the cellular immune response engendered in MCM vaccinated with CyCMV/SIV vaccine vectors. In specific aim 2, we will measure the ability of CyCMV/SIV to protect MCM from pathogenic SIV replication following low dose challenge. In specific aim 3, we will examine whole blood RNA transcriptomic profiles to identify correlates of immune protection. Successful completion of these studies will further our understanding of the unique protection afforded by CMV vectors and facilitate successful clinical translation of CMV as a prophylactic HIV vaccine.

项目概要 目前全世界有 3600 万艾滋病毒感染者，开发一种预防性艾滋病毒疫苗可以保护 防止性传播仍然是全球卫生的首要任务。基于HIV疫苗的临床前方法 表达 SIV 抗原 (RhCMV/SIV) 的恒河猴巨细胞病毒 68-1 株可引发细胞独特的 非常规 MHC 限制性 T 细胞反应，能够严格控制并最终清除 约 50% 接种疫苗的恒河猴 (RM) 中存在致病性 SIV 复制。然而，目前尚不清楚是否 68-1 RhCMV 诱导的独特免疫力和针对 SIV 的保护是 RM 特异性现象。调查 这个问题作为将 RhCMV 作为 HIV 疫苗成功转化为临床的一种手段，我们将 使用毛里求斯食蟹猴 (MCM) 概括这些结果，毛里求斯食蟹猴是一种非人类灵长类动物， 反映人类免疫遗传学的独特 MHC 遗传学。在具体目标 1 中，我们将表征细胞 使用 CyCMV/SIV 疫苗载体接种的 MCM 中产生的免疫反应。在具体目标2中，我们将 测量低剂量后 CyCMV/SIV 保护 MCM 免受致病性 SIV 复制的能力 挑战。在具体目标 3 中，我们将检查全血 RNA 转录组图谱，以确定以下各项的相关性： 免疫保护。成功完成这些研究将进一步加深我们对独特的理解 CMV 载体提供的保护并促进 CMV 作为预防性 HIV 的成功临床转化 疫苗。