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

描述(申请人提供)：目前全世界有3400万艾滋病毒携带者，开发预防性艾滋病毒疫苗仍然是全球卫生工作的重中之重。最近，一种基于CMV的疫苗方法对病原性SIV复制提供了显著的保护，保护了约50%的恒河猴。在这些受保护的动物中，我们观察到了CMV诱导的SIV特异性CD8+T细胞反应，这些反应在表型和功能上都不同于迄今研究的任何其他疫苗方案产生的CD8+T细胞，包括自然感染。CMV诱导的CD8+T细胞反应的大小与对SIV复制的深刻保护有关，值得注意的是，MHC-I可能不会限制这些反应。然而，猕猴表现出非常复杂的MHC遗传学，从而混淆了对这些保护性的、由CMV诱导的CD8+T细胞反应的研究。相比之下，毛里求斯食蟹猴(MCM)是种群瓶颈事件的后代，表现出简化的MHC遗传学，只有7种完全描述的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。在特定的目标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限制性。在特定的目标2中，我们将证实CMV诱导的CD8+T细胞保护MCM免受SIV攻击，并在体外病毒抑制试验中测量这些T细胞抑制病毒的能力。如果 如果成功，我们可以使用这种简化的非人类灵长类动物来充分剖析CMV诱导的SIV保护机制，进而为基于这些新表位的新型预防性HIV疫苗的设计提供信息。

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.