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，每年约有50,000人感染。尽管艾滋病的治疗取得了进展，2007年全世界仍有200万人死于这种疾病。在HIV/AIDS研究中，主要的非人灵长类动物模型是恒河猴，它在感染SIV后发展为类人猿艾滋病。在人类和恒河猴中，已经证明宿主遗传变异可以提供对艾滋病进展的抵抗力或易感性。然而，作为艾滋病毒/SIV的非自然宿主，人类和恒河猴没有时间适应特定的机制来预防艾滋病，而人类和恒河猴种群中存在的那些保护性遗传变异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，并通过自然选择无情地塑造，以获得强大的遗传机制，以抑制SIV感染后的疾病进展。因此，在自然宿主SIV中识别这些强大的遗传机制将揭示如何抑制艾滋病的有效解决方案。本R21的目标是确定在SIV的自然宿主——黑白眉猴中进化出抑制艾滋病进展的遗传机制的候选者。为此，我们将描述和比较黑白脸猴和恒河猴两种非人类灵长类动物在SIV感染后疾病进展差异的两个令人注目但尚未探索的候选机制：SIV感染过程中的微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感染和未感染的白嘴鸦和恒河猴之间的miRNA表达谱；2)使用阵列CGH识别拷贝数不同的白嘴鸦和恒河猴之间的基因，作为鉴定这些物种对艾滋病进展的易感性/抗性遗传基础的特定miRNA和候选基因的手段。总之，一项全面的基因组研究将用于确定候选遗传因素，这些遗传因素已经进化到抑制这种疾病的非人类灵长类动物模型中的艾滋病。

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.