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: 7755496
• 负责人: Welkin E Johnson
• 金额: $ 43.38万
• 依托单位: HARVARD MEDICAL SCHOOL
• 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/7755496
• 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; Immune system; Individual; Infection; Infectious Agent; Investigation; Knowledge; Laboratories; Lead; Light; 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; public health relevance; 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）：从长远来看，理解，管理和治疗传染病不仅需要对传染病药物的理解，而且还需要对宿主易感性的基本遗传学的理解。这包括自适应免疫系统的基因，但同样重要的是那些与病毒大分子直接相互作用的因素，要么是复制的正辅因子，要么是逃避或衰减感染的内在宿主机制。感染，疾病病程和发病机理的敏感性的可变性很大程度上是由于多个基因座遗传变异的综合作用。 Trim5alpha蛋白充当逆转录病毒复制的固有抑制剂，而灵长类动物Trim5基因座则表现出异常高的种间差异，与强阳性选择的进化史一致。我们发现，在两种与艾滋病毒/艾滋病研究，鼠尾草猕猴和烟熏芒果的两种地理上不同的旧世界猴子的Trim5alpha编码序列中存在广泛的物种内部变化或多态性变化。该提案的具体目的是通过利用非人类灵长类动物中广泛的，天然发生的适应性变化的目的统一的，以深入了解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，对TRIM51介导的限制的机制进行特定的了解，并改善对HIV/AIDS实验模型的使用。此外，结果将为HIV-1感染后阶段的新型抑制剂的发展提供深入了解。