Cross-Species transmission and adaptation of primate lentiviruses

描述(由申请人提供)：从长远来看，了解、管理和治疗传染病不仅需要了解传染病病原体，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直接与病毒大分子相互作用的因子，要么作为积极的复制辅助因子，要么作为逃避或减弱感染的内在宿主机制。感染易感性、病程和发病机制的差异在很大程度上是由于多个基因位点的遗传变异的综合影响。TRIM5α蛋白是逆转录病毒复制的内在抑制因子，灵长类TRIM5基因座表现出异常高度的物种间差异，与强烈正向选择的进化史相一致。我们发现，在与艾滋病毒/艾滋病研究特别相关的两个地理上不同的东半球猴子物种的TRIM5pha编码序列中，存在着广泛的物种内变异或多态性，这两个物种是恒河猴和乌贼。这项建议的具体目的是为了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TRIM5pha的结构和功能，并确定TRIM5pha对病毒复制和体内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基因变异如何影响病毒感染的理解，为TRIM51介导的限制机制提供具体的见解，并导致改进艾滋病毒/艾滋病实验模型的使用。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洞察力。

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.