Complete genomic DNA sequence of the sooty mangabey MHC

乌白眉猴 MHC 的完整基因组 DNA 序列

• 批准号: 8018373
• 负责人: DANIEL E. GERAGHTY
• 金额: $ 63.54万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-15 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018373
• 关键词: Acquired Immunodeficiency Syndrome; Africa; African; Animal Model; Antigens; Basic Science; Benign; Biological; Cercocebus atys; Cercopithecus aethiops; Cercopithecus pygerythrus; Chronic; Clinical Research; Communities; Complex; DNA Sequence; Data; Disease; Doctor of Philosophy; Fred Hutchinson Cancer Research Center; Future; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic screening method; Genome; Genomic Library; Genomics; HIV; HIV-1; HIV-2; Health; Human; Human Genome Project; Immune Response Genes; Immune response; Immunologic Deficiency Syndromes; Individual; Infection; Laboratories; Location; Macaca; Macaca mulatta; Major Histocompatibility Complex; Methods; Phase; Phenotype; Population; Principal Investigator; Property; Research; Resources; SIV; Screening procedure; Seroprevalences; Structure; Technology; Time; Universities; Vaccine Design; Virus Diseases; Washington; comparative; cost; nonhuman primate; receptor; research study; transmission process

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.

描述（由申请人提供）：Simian免疫缺陷病毒（SIV）自然会感染各种非人类起源的非人类灵长类动物。 SIV血清阳性在一些烟灰芒果（Cercocebus atys atys atys）中特别高。 SIV与人类免疫缺陷病毒（HIV）具有许多结构和生物学特性，但它们很少在自然宿主中引起辅助。同一SIV分离物在一种物种中诱导疾病的能力以及在另一种物种中的慢性但良性感染的能力的基础的原因是宿主遗传因素很少被表征。这些遗传因素的一个主要组成部分是主要的组织兼容性复合物（MHC），其中MHC I和II类抗原呈现基因驻留在其中，以及其他大量基因，包括一些控制MHC-I和-II表达和基因，在宿主免疫反应中涉及其他方式。正如人类基因组项目已经表现出多次的那样，框架基因组DNA序列的建立可以为大量基本和临床研究提供基本的支持和扩展，这些研究正在推动人类健康。然而，正如人类基因组项目还表明的那样，建立了携带免疫反应基因（包括MHC区域）的基因组区域的框架DNA序列，这是困难的，并且在很大程度上被这些努力所忽略了。我们建议将测序技术中的市售进步与被证明产生高质量基因组序列的方法相结合，以产生索特·曼加比MHC的完整阶段基因组DNA序列，作为未来研究的资源，包括与恒河猴猕猴MHC序列进行比较分析，我们先前完成了。这样的资源将为遗传因子的功能测试提供一个方向，这些遗传因素与恒河猕猴中SIV感染的长期不存在，然后与人类中HIV-1感染的相同表型相关。控制人类中HIV-1感染的病因宿主遗传因素的鉴定将对疾病治疗以及疫苗设计具有重要意义。为了实现这些目标，我们建议执行以下特定目的：（1）从烟熏曼加贝（Sooty Mangabey）中得出主要组织相容性复合物（MHC）和杀手Ig样受体（KIR）区域的完整和高质量的基因组序列。 （2）注释并提供派生的序列，重点是与SIV研究社区相关。 公共卫生相关性（由申请人提供）：猿猴免疫缺陷病毒（SIV）自然感染各种非人类灵长类动物，并与人类免疫缺陷病毒（HIV）共享许多结构和生物学特性（HIV），但很少在其自然宿主中引起艾滋病。我们建议生产烟熏Mangabey主要组织相容性复合物（MHC）的完整的分阶段基因组DNA序列，作为使用人类HIV-1感染动物模型的未来研究资源。该资源将有助于确定控制人类HIV-1感染的病因宿主遗传因素，从而为疾病治疗以及疫苗设计提供方向。