Cross-species transmission and adaptation of primate lentiviruses

 描述(由申请人提供)：治疗和预防传染病不仅需要了解感染病原体，还需要了解控制宿主易感性的潜在遗传学。传统上，这相当于关注适应性免疫系统的基因。然而，同样重要的是那些直接与病毒大分子相互作用的细胞因子，既可以作为病毒复制的积极辅助因子，也可以作为抑制病毒感染的内在宿主机制。后者包括“限制因素”--TRIM5、APOBEC3、BST2/tetherin、SAMHD1、Schlafen-11和MX2是研究得很好的例子。虽然单独的限制因素已经被广泛地孤立地研究(典型的是在异源细胞系中过度表达)，但它们在宿主有机体和宿主群体水平上的联合影响还没有被仔细研究。虽然这些限制因子在细胞培养中的抗病毒活性与在自然界中防止灵长类慢病毒跨物种传播的作用是一致的，但几乎没有数据直接支持TIS假说。在这项提议中，我们将使用为研究RNA病毒群体而定制的下一代测序和生物信息学工具的组合(目标1和3)来跟踪灵长类慢病毒在适应非本地宿主(猕猴的SIVsmm)的早期阶段的进化；并根据相对病毒适合度的抗性的进化后果来建立个体限制的生物学意义(目标2)。

 DESCRIPTION (provided by applicant): Treating and preventing infectious disease requires not just an understanding of the infectious agent, but also of the underlying genetics governing susceptibility of the host. Traditionally, this amounted to a focus on genes of the adaptive immune system. However, equally important are those cellular factors that interact directly with viral macromolecules, either as positive cofactors for virus replication, or as intrinsic host mechanisms for suppressing viral infection. The latter includes the "restriction factors" - with TRIM5, APOBEC3, BST2/tetherin, SAMHD1, Schlafen-11 and Mx2 being well-studied examples. While individual restriction factors have been extensively studied in isolation (typicall by overexpression in heterologous cell lines), their combined impact at the level of the host organism and the host-population has not been carefully examined. While the antiviral activity of these restriction factors in cell culture is consistent with a role in preventing cross-species transmission of primate lentiviruses in nature, there are little-to-no data that directly support tis hypothesis. In this proposal, we will track the evolution of primate lentiviruses during the earliet stages of adapting to a non-native host (SIVsmm in rhesus macaques) using a combination of next- generation sequencing and bioinformatics tools customized for studying RNA virus populations (AIMS 1 & 3); and establish the biological significance of individual restrictions in terms of the evolutionary consequences of resistance for relative viral fitness (AIM 2).