GENETICS OFNEUROPATHOGENIC SIV INFECTION

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 猴慢病毒SIVsmmFGb诱导90例神经系统疾病  100%感染的猪尾猕猴，是中枢神经系统（CNS）HIV感染的可靠模型。 关于在感染的早期阶段CNS的定殖以及随后的宿主适应性免疫应答如何影响该病毒的遗传多样性，人们知之甚少。 同样未知的是，SIVsmmFGb是否在早期感染期间在CNS组织之间形成不同的遗传区室，以及这些遗传区室是否在宿主适应性免疫应答开始后保留。 CNS的初始接种降低了Env V1区域和Int的遗传多样性，但对Nef的影响较小。 宿主适应性免疫改变了所有组织中Env V1区域和Int的遗传多样性，但Nef的结果更具多样性。 在CNS的初始接种后，SIVsmmFGb env V1区、nef和int序列各自在所研究的大多数CNS组织之间形成不同的遗传区室，这些区室随着适应性免疫的发生而基本保持不变。 在中枢神经系统初始接种期间，env V1区隔室的形成是由于正选择，而负选择则驱动了nef和int隔室的形成。 选择通过适应性免疫反应继续进行，在一些CNS组织中，所有三种基因的选择压力都在增加。 在感染过程中，env V1区在大多数车厢进行了趋同进化，与nef类似的结果。 相反，int在大多数隔间中经历了不同的进化。 在感染过程中，Env V1区和间隔之间的功能差异减少，而间隔之间的Nef功能差异则净增加。 我们的研究结果提供了对慢病毒在CNS中的播种和进化的深入了解，这可能适用于HIV感染中的类似过程。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The simian lentivirus SIVsmmFGb induces neurological disease in 90  100% of infected pigtailed macaques and is a reliable model of HIV infection of the central nervous system (CNS). Little is understood about how colonization of the CNS during the early stages of infection, and subsequent host adaptive immune responses, affect the genetic diversity of this virus. Also unknown is whether SIVsmmFGb forms distinct genetic compartments between CNS tissues during early infection and whether these genetic compartments remain following the onset of host adaptive immune responses. The initial seeding of the CNS reduced the genetic diversity of the Env V1 region and Int, but had less of an effect on Nef. Host adaptive immunity altered the genetic diversity of the Env V1 region and Int in all tissues, but results were more variable for Nef. Following initial seeding of the CNS, SIVsmmFGb env V1 region, nef and int sequences each formed distinct genetic compartments between most of the CNS tissues studied, compartments that remained largely unchanged with the onset of adaptive immunity. Formation of env V1 region compartments during initial seeding of the CNS was due to positive selection, while negative selection drove formation of the nef and int compartments. Selection continued through the adaptive immune response, with selective pressure increasing on all three genes in some CNS tissues. Over the course of infection, the env V1 regions in most compartments underwent convergent evolution, with similar results for nef. Conversely, int underwent divergent evolution in most compartments. Functional differences in env V1 region and int between compartments decreased over the course of infection, while nef functional differences between compartments saw a net increase. Our results provide insight into lentivirus seeding and evolution in the CNS that may be applicable to similar processes in HIV infection.