A universal MHC-E-restricted T cell vaccine for HIV

 目前全球有3400万人感染艾滋病毒，开发预防性艾滋病毒疫苗以防止异性传播仍然是全球卫生的首要任务。我们最近发现了一类新的CD 8 + T细胞的存在，识别由非经典分子MHC-E呈递的肽抗原。与人类群体中存在的经典HLA-A、-B和-C等位基因的惊人多样性相反，仅存在两种HLA-E等位基因，其仅相差一个氨基酸并且功能相同。此外，虽然经典的HLA-A和-B分子被Nef蛋白从HIV感染细胞的表面去除，但HLA-E表面表达显著增加。这些理想的特性提高了靶向HLA-E的疫苗可以诱导通用T细胞应答的可能性，该通用T细胞应答将不受Nef蛋白的免疫逃避活性的影响，并且由所有接种疫苗的个体共享。为了研究这一有趣的想法，我们将在本提案的具体目标1中定义人类和恒河猴中的MHC-E限制性CD 8 + T细胞表位。在具体目标2中，我们将表征这些不寻常的T细胞的功能性、TCR使用和抗病毒功效。在具体的目标3中，我们将用一种新的疫苗方法接种猕猴，该疫苗方法同时递送SIV抗原和经鉴定可触发MHC-E呈递的病毒蛋白。我们随后将用低剂量SIV攻击这些动物，以确定MHC-E限制性CD 8 + T细胞的保护能力。这些研究的成功完成可以定义一种全新的方法，通过动员单态MHC-E分子来诱导普遍的保护性免疫。

 DESCRIPTION (provided by applicant): With 34 million people currently living with HIV worldwide, developing a prophylactic HIV vaccine that protects against heterosexual transmission remains a top global health priority. We have recently discovered the existence of a novel class of CD8+ T cells recognizing peptide antigen presented by the non-classical molecule MHC-E. In contrast to the staggering diversity of classical HLA-A, -B, and -C alleles present in the human population, only two HLA-E alleles exist, which differ only by one amino acid and are functionally identical. Furthermore, while classical HLA-A and -B molecules are removed from the surface of HIV-infected cells by the Nef protein, HLA-E surface expression increases dramatically. These desirable traits raise the possibility that a vaccine targeting HLA-E could induce a universal T cell response, which would be unaffected by the immune evasion activities of the Nef protein, and shared by all vaccinated individuals. To investigate this intriguing idea, we will define MHC-E restricted CD8+ T cell epitopes in both humans and rhesus macaques in specific aim 1 of this proposal. In specific aim 2, we will characterize the functionality, TCR usage, and antiviral efficacy of these unusual T cells. In specific aim 3, we wil vaccinate macaques with a novel vaccine approach that delivers SIV antigens simultaneously with viral proteins identified to trigger MHC-E presentation. We will subsequently challenge these animals with low-dose SIV to determine the protective capability of MHC-E-restricted CD8+ T cells. Successful completion of these studies could define an entirely new approach to inducing universal protective immunity by mobilizing the monomorphic MHC-E molecule.