Complete genomic DNA sequence of the sooty mangabey MHC

描述（由申请方提供）：猴免疫缺陷病毒（SIV）自然感染多种非人非洲灵长类动物。SIV血清阳性率在部分白眉猴群体中特别高。虽然SIV与人类免疫缺陷病毒（HIV）有许多共同的结构和生物学特性，但它们很少在其天然宿主中诱导AIDS。同一SIV分离株能够在一个物种中诱导疾病并在另一个物种中诱导慢性但良性感染的致病因素是宿主遗传因素，在很大程度上很少被表征。这些遗传因子的中心组分是主要组织相容性复合物（MHC），其中存在MHC I类和II类抗原呈递基因，以及大量其他基因，包括控制MHC-I和-II表达的一些基因和以其他方式参与宿主免疫应答的基因。正如人类基因组计划多次表明的那样，框架基因组DNA序列的建立可以为目前正在促进人类健康的大量基础和临床研究提供基本支持和扩展。然而，正如人类基因组计划也表明的那样，建立携带免疫应答基因的基因组区域（尤其包括MHC区域）的框架DNA序列是困难的，并且在很大程度上被这些努力所忽视。我们建议结合联合收割机商业上可获得的测序技术的进步与方法证明，生产高质量的基因组序列，以产生一个完整的分阶段的白眉猴MHC基因组DNA序列作为未来研究的资源，包括与恒河猴MHC序列，我们以前完成的比较分析。这样的资源将提供一个方向的功能测试的遗传因素，涉及到长期的非进展的SIV感染恒河猴，然后在人类中的HIV-1感染的相同表型。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产生重要影响。为了实现这些目标，我们提出了以下具体目标：（1）获得完整的和高质量的基因组序列的主要组织相容性复合体（MHC）和杀手免疫球蛋白样受体（KIR）的区域从mangabey。(2)注释并提供衍生序列，重点是与SIV研究界的相关性。 公共卫生相关性（由申请人提供）：猴免疫缺陷病毒（SIV）自然感染多种非人灵长类动物，并与人类免疫缺陷病毒（HIV）具有许多结构和生物学特性，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分阶段的mangabey主要组织相容性复合体（MHC）的基因组DNA序列作为未来研究的资源，使用人类HIV-1感染的动物模型。这一资源将有助于确定控制人类HIV-1感染的致病宿主遗传因素，为疾病治疗和疫苗设计提供指导。

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.