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: 10398872
• 负责人: Scott G Hansen
• 金额: $ 79.59万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398872
• 关键词: Alleles; Animals; Antigens; Bioinformatics; Blood specimen; CD8-Positive T-Lymphocytes; Cells; Cellular Immunity; Clinic; Complex; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Development; Dose; Dose Limiting; Effectiveness; Endothelial Cells; Event; Exhibits; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; HIV; HIV vaccine; HIV-1; Health Priorities; Human; Immune; Immune response; Immunity; Immunogenetics; Immunologics; Individual; Infection; Macaca; Macaca fascicularis; Macaca mulatta; Maps; Measures; Mediating; MicroRNAs; Modeling; Monitor; Pathogenicity; Persons; Phase; Plasma; Population; Positioning Attribute; Property; RNA; Recording of previous events; Research; Rhesus; Role; SIV; SIV Vaccines; Sexual Transmission; Site; T cell response; Tissues; Translations; Vaccinated; Vaccines; Variant; Viral Load result; Viremia; Whole Blood; 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.

项目摘要 目前全世界有3600万人感染艾滋病毒，开发一种预防性艾滋病毒疫苗， 防止性传播仍然是全球卫生的首要优先事项。一种临床前HIV疫苗方法， 表达SIV抗原的恒河猴巨细胞病毒68-1株（RhCMV/SIV）细胞特异性 非常规的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）中的致病性SIV复制。然而，目前尚不清楚， 68-1 RhCMV诱导的对SIV的独特免疫和保护是RM特异性现象。探讨 这个问题作为一种手段，成功地翻译RhCMV进入临床作为艾滋病毒疫苗，我们将 使用一只非人灵长类动物食蟹猴（MCM）来概括这些结果， 独特的MHC基因反映了人类免疫遗传学。在具体目标1中，我们将表征细胞 用CyCMV/SIV疫苗载体接种MCM产生免疫应答。具体目标2： 测量CyCMV/SIV在低剂量后保护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转录组学谱，以鉴定以下相关性： 免疫保护。成功完成这些研究将进一步加深我们对独特的 CMV载体提供的保护，并促进CMV作为预防性HIV的成功临床翻译 疫苗