Understanding Unconventional CD8+ T cell Responses in Protection from HIV

项目摘要 目前全球有3600万艾滋病毒携带者，正在开发一种预防性艾滋病毒疫苗，以保护 防止性传播仍然是全球卫生工作的重中之重。一种临床前HIV疫苗接种方法 表达SIV抗原的猕猴巨细胞病毒68-1株(RhCMV/SIV)诱导细胞特异性 非常规的MHC限制性T细胞反应，能够严格控制并最终清除 在接种疫苗的恒河猴(RM)中，约50%的猕猴体内存在病理性SIV复制。然而，目前仍不清楚 68-1RhCMV诱导的特异性免疫和对SIV的保护是一种RM特有的现象。去调查 这个问题作为成功将人巨细胞病毒作为HIV疫苗推向临床的一种手段，我们将 用毛里求斯食蟹猴(MCM)来概括这些结果，MCM是一种非人类灵长类物种，具有 反映人类免疫遗传学的独特MHC遗传学。在特定的目标1中，我们将描述细胞 CyCMV/SIV疫苗载体免疫MCM后产生免疫应答。在具体目标2中，我们将 检测CyCMV/SIV对小剂量致病性SIV复制的保护作用 挑战。在特定的目标3中，我们将检查全血RNA转录图谱，以确定与 免疫保护。这些研究的成功完成将进一步加深我们对 CMV载体提供的保护和促进CMV作为预防性HIV的临床成功转化 疫苗。

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.