Genomic characterization of a nonhuman primate model for AIDS research

描述（由申请人提供）：估计有 100 万美国人感染艾滋病毒，每年还有约 50,000 人感染艾滋病毒。尽管艾滋病治疗取得了进展，2007 年全世界仍有约 200 万人死于这种疾病。 HIV/AIDS 研究中主要的非人类灵长类动物模型是恒河猴，它在感染 SIV 后会患上猿猴艾滋病。在人类和恒河猴中，已证明宿主遗传变异可以对艾滋病的进展提供抵抗力或易感性。然而，作为 HIV/SIV 的非自然宿主，人类和恒河猴还没有时间适应预防艾滋病的特定机制，而人类和猕猴群体中存在的那些保护性基因变异很可能是过去与其他传染病相关的选择的遗迹。相比之下，SIV 天然宿主的基因组与病毒共同进化，并通过自然选择不断塑造，以获得强大的遗传机制来抑制 SIV 感染后的疾病进展。因此，在自然宿主 SIV 中鉴定出这些强大的遗传机制将为抑制艾滋病提供行之有效的解决方案。 R21 的目标是确定遗传机制的候选者，这些遗传机制已经进化到抑制 SIV 自然宿主（乌白白眉猴）进展为艾滋病。为此，我们将描述和比较乌白眉猴和恒河猴，这两种非人灵长类动物感染 SIV 后疾病进展的差异的两个引人注目但尚未探索的候选机制：SIV 感染过程中的微小 RNA (miRNA) 表达谱，以及这些物种之间基因拷贝数的差异。具体来说，我们将：1) 表征和比较 SIV 感染和未感染的白眉猴和恒河猴之间的 miRNA 表达谱，以及 2) 使用阵列 CGH 来识别白眉猴和恒河猴之间拷贝数不同的基因，作为识别特定 miRNA 和基因的方法，这些 miRNA 和基因是这些物种中艾滋病易感性/抵抗性遗传基础的候选基因。总之，一项全面的基因组研究将用于识别在非人类灵长类动物模型中进化出抑制艾滋病的候选遗传因子。 公共卫生相关性：非人类灵长类动物是研究艾滋病疾病进展的独特遗传资源。该项目的目标是表征和比较艾滋病研究中使用的两个密切相关的模型物种的基因组特性，作为识别可抑制艾滋病毒感染者疾病进展的遗传机制的手段。

DESCRIPTION (provided by applicant): An estimated 1 million Americans are infected with HIV and another ~50,000 are infected each year. Despite progress in the treatment of AIDS, in 2007 ~2 million people around the world died from this disease. The primary nonhuman primate model in HIV/AIDS research is the rhesus macaque which develops simian-AIDS after infection with SIV. In both humans and rhesus macaques it has been demonstrated that host genetic variation can provide resistance or susceptibility to the progression to AIDS. However, as non-natural hosts of HIV/SIV, humans and rhesus macaques have not had time to adapt specific mechanisms to prevent AIDS, and those protective genetic variants that are present in the human and macaque populations are likely relics of past selection related to other infectious diseases. In contrast, the genomes of natural hosts of SIV have co-evolved with the virus and been relentlessly shaped by natural selection to acquire robust genetic mechanisms to suppress disease progression after SIV infection. Thus, identification of those robust genetic mechanisms in a natural host SIV would reveal a proven solution for how to suppress AIDS. The goal of this R21 is to identify candidates for the genetic mechanisms that have evolved to suppress progression to AIDS in a natural host of SIV, the sooty mangabey. To do so we will characterize and compare the sooty mangabey and rhesus macaque with respect to two compelling but unexplored candidate mechanisms for the difference in disease progression after SIV infection in these two nonhuman primates: micro RNA (miRNA) expression profiles during the course of SIV infection, and differences in gene copy number between these species. Specifically, we will: 1) characterize and compare the miRNA expression profiles between SIV- infected and uninfected sooty mangabeys and rhesus macaques, and 2) use array CGH to identify genes that differ in copy number between sooty mangabey and rhesus macaque as the means to identify specific miRNAs and genes that are candidates for the genetic basis of susceptibility/resistance to the progression to AIDS in these species. In summary, a comprehensive genomic study will be used to identify candidate genetic factors that have evolved to suppress AIDS in a nonhuman primate model of this disease. PUBLIC HEALTH RELEVANCE: Nonhuman primates are a unique genetic resource for studying disease progression to AIDS. The goal of this project is to characterize and compare the genomic properties of two closely-related model species used in AIDS research as a means to identify genetic mechanisms that can suppress disease progression in HIV- infected individuals.