Complete genomic DNA sequence of the sooty mangabey MHC

描述(申请人提供)：猴免疫缺陷病毒(SIV)自然感染非洲起源的各种非人类灵长类动物。SIV血清阳性率在一些乌龟(Cercocebus Atys Atys)中尤其高。虽然SIV与人类免疫缺陷病毒(HIV)有许多结构和生物学特性，但它们很少在自然宿主中引发艾滋病。同一SIV分离株在一个物种中诱发疾病的能力以及在另一个物种中慢性但良性感染的基础上的致病因素是宿主遗传因素，在很大程度上很少被描述。这些遗传因子的中心成分是主要组织相容性复合体(MHC)，MHC I和II类抗原呈递基因与大量其他基因一起存在，包括一些控制MHC-I和-II表达的基因，以及以其他方式参与宿主免疫反应的基因。正如人类基因组计划多次表明的那样，框架基因组DNA序列的建立可以为大量的基础和临床研究提供基本支持和扩展，这些研究现在正在促进人类健康。然而，正如人类基因组计划也表明的那样，为包含免疫反应基因的基因组区域，特别是MHC区域建立框架DNA序列是困难的，而且在很大程度上被这些努力忽视了。我们建议将商业上可获得的测序技术的进步与已被证明能产生高质量基因组序列的方法相结合，以产生一个完整的阶段性黑尾猴MHC基因组DNA序列，作为未来研究的资源，包括与我们之前完成的恒河猴MHC序列的比较分析。这样的资源将为遗传因素的功能测试提供方向，这些遗传因素与恒河猴SIV感染的长期无进展有关，进而为人类感染HIV-1的相同表型提供方向。确定控制人类HIV-1感染的致病宿主遗传因素将对疾病治疗和疫苗设计具有重要意义。为了实现这些目标，我们提出了以下具体目标：(1)从烟色山竹中获得完整和高质量的主要组织相容性复合体(MHC)和杀伤分子Ig样受体(KIR)区域的基因组序列。(2)注释和提供衍生序列，强调与SIV研究社区的相关性。 公共卫生相关性(申请人提供)：猴免疫缺陷病毒(SIV)自然感染各种非人类灵长类动物，并具有许多与人类免疫缺陷病毒(HIV)相同的结构和生物学特性，但很少在其自然宿主中诱导艾滋病。我们建议生产一个完整的阶段的基因组DNA序列的煤质芒果主要组织相容性复合体(MHC)作为资源，为未来的研究使用动物模型的人类艾滋病毒-1感染。这一资源将有助于确定控制人类感染HIV-1的致病宿主遗传因素，为疾病治疗以及疫苗设计提供方向。

DESCRIPTION (provided by applicant): Simian immunodeficiency viruses (SIV) naturally infect a variety of nonhuman primates of African origin. SIV seroprevalence is particulariy high in some troops of sooty mangabeys (Cercocebus atys atys). While SIV share many structural and biological properties with human immunodeficiency viruses (HIV), they rarely induce AIDS in their natural hosts. The causative factors that underlie the ability of the same SIV isolate to induce disease in one species and a chronic but benign infection in another species are host genetic factors that have to a large extent been little characterized. A central component of these genetic factors is the Major Histocompatibiltiy Complex (MHC), within which the MHC class I and II antigen-presenting genes reside, alongside a large number of other genes, including some that control MHC-I and -II expression and genes that are in other ways involved in the host immune response. As the human genome project has shown many times over, the establishment of framework genomic DNA sequences can provide fundamental support for, and extension of, a plethora of basic and clinical research studies that are now advancing human health. However, as the human genome project has also shown, establishing framework DNA sequences for regions of the genome harboring immune response genes, including notably the MHC region, is difficult and has largely been ignored by those efforts. We propose to combine commercially available advancements in sequencing technology with methods proven to produce high quality genomic sequence to yield a completed phased genomic DNA sequence of the sooty mangabey MHC as a resource for future studies, including comparative analysis with the rhesus macaque MHC sequence, which we previously completed. Such a resource will provide a direction for functional testing of genetic factors that relate to long- term nonprogression of SIV infection in rhesus macaques, and then to the same phenotype for HIV-1 infection in humans. The identification of causative host genetic factors that control HIV-1 infection in humans would have important implications for disease treatment as well as for vaccine design. To accomplish these objectives we propose to carry out the following specific aims: (1) To derive complete and high quality genomic sequences of the major histocompatibility complex (MHC) and killer Ig-like receptor (KIR) regions from the sooty mangabey. (2) To annotate and make available the derived sequences with an emphasis towards relevance to the SIV research community. PUBLIC HEALTH RELEVANCE (provided by applicant): Simian immunodeficiency viruses (SIV) naturally infect a variety of nonhuman primates and share many structural and biological properties with human immunodeficiency viruses (HIV), but rarely induce AIDS in their natural hosts. We propose to produce a completed phased genomic DNA sequence of the sooty mangabey major histocompatibility complex (MHC) as a resource for future studies using animal models of human HIV-1 infection. This resource will contribute to identifying causative host genetic factors controlling HIV-1 infection in humans, providing direction for disease treatment as well as for vaccine design.