Immunogenetics of Macaques Used for Biodefense and AIDS Research

描述（申请人提供）：猕猴是艾滋病疫苗开发中最重要的动物模型，越来越多地用于生物防御研究。一个人的免疫遗传学可以深刻地影响对艾滋病病毒和其他病原体的易感性。源自印度的恒河猴具有最彻底的免疫遗传学特征；然而，它们在研究中的可用性非常有限。中国猕猴、食蟹猕猴和长尾猕猴越来越多地被用来缓解印度猕猴的短缺。随着对这些猕猴的研究越来越普遍，有一种新的认识是，在特定的研究中，它们可能比来自印度的恒河猴具有令人信服的优势。为了研究细胞对艾滋病病毒的免疫和生物防御，需要全面了解主要组织相容性复合体（MHC）和杀伤免疫球蛋白受体（KIR）的遗传学。在本项目初期，我们对来自不同来源的食蟹猕猴的MHC I类和II类等位基因进行了测序，并确定了食蟹猕猴的第一个MHC肽结合基序。在本次更新中，我们将继续并扩展该项目，完成：Specific Aim 1，对食蟹猴、中国恒河猴和长尾猕猴中常见表达的MHC I类和II类等位基因进行测序。特异性目标2，其中全长KIR等位基因将从相同的猕猴种群测序。特异性Aim 3，其中将确定8个MHC I类和8个MHC II类肽结合基序。这些目标将利用高通量“下一代”DNA测序的最新发展，快速表征全长MHC和KIR等位基因。将鉴定至少300个迄今为止新的MHC类，150个MHC II类和300个KIR序列。研究小组在猕猴免疫遗传学、深度测序和MHC生物化学方面的经验使他们有资格继续这项重要的研究。

DESCRIPTION (provided by applicant): Macaque monkeys are the most important animal model for AIDS vaccine development and are increasingly being used in biodefense research. An individual's immunogenetics can profoundly influence susceptibility to AIDS viruses and other pathogens. Indian-origin rhesus macaques have the most thoroughly characterized immunogenetics; however, their availability for research is extremely limited. Chinese-origin rhesus macaques, cynomolgus macaques, and pig-tailed macaques are increasingly relied upon to alleviate the shortage of Indian- rhesus macaques. As studies with these macaques become more common, there is a newfound appreciation that they may offer compelling advantages over Indian-origin rhesus macaques for specific studies. To study cellular immunity to AIDS viruses and biodefense, a comprehensive understanding of major histocompatibility complex (MHC) and killer immunoglobulin receptor (KIR) genetics is required. In the initial project period of this grant, MHC class I and II alleles were sequenced from cynomolgus macaques from different origins and the first MHC peptide binding motifs in cynomolgus macaques were determined. In this renewal, we will continue and expand this project by completing: Specific Aim 1, in which commonly expressed MHC class I and II alleles will be sequenced from cynomolgus, Chinese rhesus, and pig-tailed macaques. Specific Aim 2, in which full length KIR alleles will be sequenced from the same populations of macaques. Specific Aim 3, in which 8 MHC class I and 8 MHC class II peptide binding motifs will be determined. These Aims will take advantage of recent developments in high-throughput 'next generation' DNA sequencing to rapidly characterize full-length MHC and KIR alleles. At least 300 heretofore novel MHC class 1,150 MHC class II, and 300 KIR sequences will be identified. The experience of the investigative team in macaque immunogenetics, deep sequencing, and MHC biochemistry uniquely qualifies them to continue this important research.