Defining non-classical, CMV-induced CD8 T cell responses

描述（由申请人提供）：目前全世界有3400万人感染艾滋病毒，开发预防性艾滋病毒疫苗仍然是全球卫生的首要优先事项。最近，一种基于cmv的疫苗方法对SIV的致病性复制提供了惊人的保护，约50%的恒河猴受到保护。在这些受保护的动物中，我们观察到cmv诱导的siv特异性CD8+ T细胞反应在表型和功能上不同于迄今为止研究的任何其他疫苗方案（包括自然感染）产生的CD8+ T细胞。这些cmv诱导的CD8+ T细胞反应的强度与SIV复制的深度保护相关，并且引人注目的是，可能不受mhc - 1的限制。然而，恒河猴表现出非常复杂的MHC遗传，从而混淆了这些保护性的cmv诱导的CD8+ T细胞反应的研究。相比之下，来自种群瓶颈事件的毛里求斯食蟹猴（MCM）表现出简化的MHC遗传，只有7个完全描述的MHC单倍型。因此，MCM是研究cmv诱导保护性免疫遗传学的理想模型。为此，我们将使用MCM来定义cmv诱导的CD8+ T细胞反应的限制性MHC分子。在特异性目的1中，我们将用表达SIV蛋白的CMV载体接种MCM，并确定CMV诱导的SIV特异性CD8+ T细胞反应的mhc限制。在特定目标2中，我们将证实cmv诱导的CD8+ T细胞保护MCM免受SIV攻击，并在体外病毒抑制实验中测量这些T细胞抑制病毒的能力。如果

DESCRIPTION (provided by applicant): With 34 million people currently living with HIV worldwide, developing a prophylactic HIV vaccine remains a top global health priority. A CMV-based vaccine approach recently provided striking protection from pathogenic SIV replication with ~50% of rhesus macaques protected. In these protected animals, we have observed CMV-induced, SIV-specific CD8+ T cell responses that are phenotypically and functionally distinct from CD8+ T cells engendered by any other vaccine regimen, including natural infection, studied to date. The magnitude of these CMV-induced CD8+ T cell responses correlates with the profound protection from SIV replication and, strikingly, may not be restricted by MHC-I. However, rhesus macaques exhibit remarkably complex MHC genetics, thereby obfuscating the study of these protective, CMV-induced CD8+ T cell responses. In contrast, Mauritian cynomolgus macaques (MCM), descendants from a population bottleneck event, exhibit simplified MHC genetics with only seven completely described MHC haplotypes. Therefore, MCM are the ideal model to study the genetics of CMV-induced protective immunity. To this end, we will use MCM to define the restricting MHC molecule for the CMV-induced CD8+ T cell responses. In specific aim 1, we will vaccinate MCM with CMV vectors expressing SIV proteins and determine the MHC-restriction of the CMV-induced, SIV-specific CD8+ T cell responses. In specific aim 2, we will confirm that CMV-induced CD8+ T cells protect MCM from SIV challenge and measure the ability of these T cells to suppress virus in in vitro viral suppression assays. If successful, we can use this MHC-simplified nonhuman primate to fully dissect the mechanism of CMV-induced protection against SIV and in turn inform the design of a novel, prophylactic HIV vaccine based on these novel epitopes.