Cross-Species transmission and adaptation of primate lentiviruses

灵长类慢病毒的跨物种传播和适应

• 批准号: 8291198
• 负责人: Welkin E Johnson
• 金额: $ 38.35万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-21 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8291198
• 关键词: AIDS Vaccines; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Alleles; Animals; Asians; Attenuated; Biological; Biology; Capsid; Capsid Proteins; Cell Line; Cells; Cercocebus atys; Cercopithecidae; Chimeric Proteins; Chronic; Code; Communicable Diseases; Complement; Cross Infection; Cyclophilin A; Development; Disease; Disease Progression; Event; Experimental Models; Family suidae; Frequencies; Future; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; HIV-1; HIV-2; Health; Immune system; Individual; Infection; Infectious Agent; Investigation; Knowledge; Laboratories; Lead; Lymphocyte; Macaca; Macaca mulatta; Maps; Mediating; Modeling; Molecular Genetics; Nature; Organism; Pathogenesis; Predisposition; Primate Lentiviruses; Primates; Protein Isoforms; Proteins; Recording of previous events; Research; Research Design; Site; Specificity; Staging; Structural Models; Structure; Subfamily lentivirinae; Surface; TRIM Gene; Tail; Testing; Tissues; Variant; Viral; Virus Diseases; Work; Zoonoses; cofactor; immortalized cell; improved; in vivo; inhibitor/antagonist; insight; mRNA Differential Displays; macromolecule; macrophage; nonhuman primate; novel; overexpression; protein function; research study; transmission process

DESCRIPTION (provided by applicant): Understanding, managing and treating infectious disease in the long-term requires not just an understanding of the infectious agent, but also of the underlying genetics governing susceptibility of the host. This includes genes of the adaptive immune system, but equally important are those factors that interact directly with viral macromolecules either as positive cofactors for replication or as intrinsic host mechanisms for evading or attenuating infection. Variability in susceptibility to infection, disease course and pathogenesis is due in large part to the combined effects of genetic variation at multiple loci. The TRIM5alpha protein functions as an intrinsic inhibitor of retroviral replication, and the primate TRIM5 locus displays an unusually high degree of interspecies divergence, consistent with an evolutionary history of strong positive selection. We have discovered that extensive within-species variation, or polymorphism, exists in the TRIM5alpha coding sequences of two geographically distinct species of old world monkeys of particular relevance to HIV/AIDS research, rhesus macaques and sooty mangabeys. The specific aims of this proposal are unified by the goal of exploiting the extensive, naturally occurring adaptive variations in nonhuman primates to gain insight into the structure and function of TRIM5alpha, and to determine the extent of TRIM5alpha's influence on viral replication and disease progression in vivo. PUBLIC HEALTH RELEVANCE: These investigations will improve our understanding of how host genetic variation impacts viral infection, provide specific insight into mechanisms of TRIM51 mediated restriction, and lead to improved use of experimental models for HIV/AIDS. Moreover, the results will provide insight into the development of novel inhibitors of the post-entry stage of HIV-1 infection.

描述（由申请人提供）：长期理解、管理和治疗传染病不仅需要了解传染原，还需要了解控制宿主易感性的潜在遗传学。这包括适应性免疫系统的基因，但同样重要的是那些与病毒大分子直接相互作用的因素，或者作为复制的正辅因子，或者作为逃避或减弱感染的内在宿主机制。感染易感性、病程和发病机制的变异在很大程度上是由于多个位点遗传变异的综合影响。 TRIM5α 蛋白作为逆转录病毒复制的内在抑制剂发挥作用，灵长类 TRIM5 基因座显示出异常高度的种间差异，这与强正选择的进化历史一致。我们发现，与艾滋病毒/艾滋病研究特别相关的两个地理不同的旧大陆猴种（恒河猴和乌白眉猴）的 TRIM5alpha 编码序列中存在广泛的种内变异或多态性。该提案的具体目标是利用非人类灵长类动物中广泛的、自然发生的适应性变异来深入了解 TRIM5alpha 的结构和功能，并确定 TRIM5alpha 对体内病毒复制和疾病进展的影响程度。 。公共卫生相关性：这些研究将提高我们对宿主遗传变异如何影响病毒感染的理解，提供对 TRIM51 介导的限制机制的具体见解，并改进 HIV/AIDS 实验模型的使用。此外，这些结果将为 HIV-1 感染进入后阶段的新型抑制剂的开发提供深入的见解。