Decryption of KIR genetics and function in early HIV-1 infection

摘要 自然杀伤(Natural Killer，NK)细胞是先天免疫反应的快速效应臂。T细胞之前的活性 应答，NK细胞在对抗HIV方面发挥关键作用，并受表面调控网络的调节 分子，其中的关键是多态的KIR(杀手免疫球蛋白样受体)。我们建议绘制基因图谱 人类白细胞抗原I类等位基因连接的NK细胞调节因子KIR基因变异与疾病的关系 一组新近感染HIV的成年人的标志物和NK细胞功能。我们的研究可能会确定NK细胞 可以调节反应，以提供一种新的预防艾滋病毒的模式。 由于其复杂性，只有一小部分KIR基因座被检查是否与疾病或功能相关 在HIV-1感染者中。关于KIR和人类白细胞抗原在HIV-1疾病中作用的研究主要集中在 KIR3DS1/KIR3DL1基因座及其可能的配体，HLABw4Ile80(I类等位基因的子集)，并产生了 结果截然不同。一些研究已经发现了相互作用授予临床保护的证据，而 其他人则没有观察到相互作用的证据。在HIV疾病中，其他KIR基因在很大程度上还没有被发现。 因此，关于KIR和NK功能在HIV中的作用，我们有有趣但不完整的信息。 为了描绘这个复杂的系统，我们将使用一种新的基于质谱学的dna测序方法。 为了绘制整个KIR基因簇和人类白细胞抗原I类A、B和C基因座与NK细胞的功能图谱(NK干扰素-g， 721.221靶细胞系统中的CD107a)和早期疾病标志物在一项对1500名成年人的大型纵向研究中 来自北美和巴西的早期艾滋病毒感染队列。我们的目标是(1)描述KIR基因簇， 1300名新近感染的成人的HLAA、B、C基因座；(2)绘制NK效应者的KIR和人类白细胞抗原基因图谱 在这1300名成年人中进行KIR/HLA遗传学和NK功能检测 HIV-1暴露于未感染的成年人。暴露于艾滋病毒的未感染组将允许评估 KIR/人类白细胞抗原对HIV-1感染的保护作用及对NK功能的影响我们的巴西 队列使我们能够进一步检查KIR和人类白细胞抗原对未经治疗的B亚型感染的影响，因为治疗不是 开始，直到CD4+计数达到300个细胞/微升。

ABSTRACT The Natural Killer (NK) cell is a rapid effector arm of the innate immune response. Active before T cell responses, NK cells play a critical role against HIV and are regulated by a network of surface regulatory molecules, key among them the polymorphic KIR (killer Ig-like receptor). We propose to map the genetic variation of KIR - a potent and polymorphic regulator of NK cells ligated by HLA Class I alleles - to disease markers and NK cell function in a cohort of recently HIV-infected adults. Our research may determine if the NK response can be modulated to confer a novel mode of protection against HIV. Due to its complexity, only a fraction of KIR loci have been examined for disease or functional associations in HIV-1 infected persons. Studies on the role of KIR and HLA in HIV-1 disease have focused on the KIR3DS1/KIR3DL1 loci and its putative ligand, HLA Bw4Ile80 (a subset of Class I alleles), and have yielded contrasting results. Some studies have found evidence of an interaction conferring clinical protection, while others have observed no evidence for an interaction. Other KIR genes are largely unexplored in HIV disease. Hence, we have intriguing but incomplete information about the role of KIR and NK function in HIV. To chart this complex system, we will employ a novel mass spectrometry-based DNA sequencing method to chart the entire KIR gene cluster and the HLA Class I A, B, and C loci to NK cell functional profile (NK IFN-g, CD107a in a 721.221 target cell system) and early disease markers in a large, longitudinal study of 1500 adults from a North American and Brazilian early HIV infection cohort. We aim (1) To describe the KIR gene cluster, and the HLA A, B and C loci in 1300 recently infected adults; (2) To chart KIR and HLA genetics to NK effector function in these 1300 adults and (3) To perform KIR/HLA genetics and NK functional assays in a group of 200 HIV-1 exposed uninfected adults. The HIV-exposed uninfected group will allow assessment of the role of KIR/HLA in protection against HIV-1 acquisition and effects of HIV-1 infection on NK function. Our Brazil cohort enables us to further examine KIR and HLA effects on untreated subtype B infection, as treatment is not initiated until a CD4+ count of 300 cells/ul.