FELINE IMMUNODEFICIENCY VIRUS INFECTION AS A MODEL FOR CNS INFECTION

这项研究的目标是进一步完善猫/FIV系统作为一种 慢病毒感染中枢神经系统的模型。我们希望确定 FIV诱导中枢神经系统功能障碍的分子基础，定义细胞 感染该病毒的人群，并对直接和 病毒作用的间接机制。我们将对一个 一系列表现出不同宿主细胞范围的野生型和突变型FIV 属性，以评估每种变种的传播程度 病毒侵入中枢神经系统和外周，以及确定宿主细胞如何 射程属性影响中枢神经系统疾病的发病率和严重程度。 待检测的FIV包括分子克隆的亲本FIV-PPR；突变体 缺乏功能性脱氧尿苷三磷酸酶(DU)基因的FIV-PPR； 一种能够高效感染神经胶质细胞的FIV-PPR的自然变体 体外培养的细胞系，以及T细胞和巨噬细胞；分子克隆 FIV-34TF10，一种源于FIV-Petala的缺乏功能的物种 ORF 2基因；以及FIV-034TF10的“突变体”，其中阅读框 对于Orf 2，已被修复。每个FIV都有不同的宿主细胞 可能导致独特的作用机制的一系列体外表型 中枢神经系统。通过与Fox组件协作，我们将使用直接 体内感染的小胶质细胞连续传代作为促进 增强FIV-PPR的“神经亲和性”，这是一种成功的手术 为福克斯博士选择神经侵袭性的SIVmac 251。我们会 还研究了病毒包膜糖蛋白的间接作用。 通过制备全长和截短形式的环境来发挥中枢神经系统的功能 FIV-P(PR、FIV-PPRglial和FIV-34TF10.这些蛋白质将 在体内应用于Henriksen组件以评估IC的影响 大鼠睡眠结构上接种病毒糖蛋白的实验研究 猫模。糖蛋白也将被用来确定是否暴露于 TO SU将影响小胶质细胞的转录模式，在 与Sutcliffe组件协作。该组件还将 为ALL提供病毒学、免疫学和感染细胞支持 其他组件，包括Phillips、Fox和Sarvetnik组件， 以及样本评估核心。这些研究将进一步推动我们的 慢病毒如何感染和扰乱中枢神经系统的知识。

The goal of this research is to further refine the feline/FIV system as a model for infection of the CNS by lentiviruses. We wish to determine the molecular basis for CNS dysfunctions induced by FIV, define the cell populations infected by the virus, and investigate both direct and indirect mechanisms for virus action. We will perform analyses of a series of wild type and mutant FIVs that exhibit distinct host cell range properties, in order to assess the extent of dissemination of each variant virus int he CNS and periphery, as well as to determine how host cell range properties influence the rate of onset and severity of CNS disease. FIVs to be tested include moleclularly cloned parental FIV-PPR; a mutant of FIV-PPR that lacks a functional deoxyuridine triphosphatase (DU) gene; a natural variant of FIV-PPR that is able to productively infect a glial cell line in vitro, as well as T cells and macrophages; molecularly cloned FIV-34TF10, a species derived from FIV-Petaluma that lacks a functional Orf 2 gene; and a "mutants:" of FIV-034TF10, in which the reading frame for Orf 2 has been repaired. Each of these FIVs has distinct host cell range phenotypes in vitro that may lead to unique mechanisms of action on the CNS. In collaboration with the Fox component, we will use direct serial passage of in vivo infected microglial cells as a means to promote enhanced "neurotropism" of FIV-PPR, a procedure that has been successful for Dr. Fox in selecting for neuroinvasive forms of SIVmac 251. We will also examine the role of indirect effects of viral Env glycoproteins on CNS function by preparing full-length and truncated forms of the Env proteins of FIV-P(PR, FIV-PPRglial, and FIV-34TF10. These proteins will be employed in vivo in the Henriksen component to assess the influence IC inoculation of viral glycoproteins on sleep architecture ina the rat and cat models. The glycoproteins will also be used to determine if exposure to SU will influence transcription patterns in microglia, performed in collaboration with the Sutcliffe component. This component will also provide virological, immunological, and infected cell support for all other components, including the Phillips, Fox, and Sarvetnik components, as well as the Specimen Assessment Core. These studies will further our knowledge of how lentiviruses infect and perturb the CNS.