FELINE IMMUNODEFICIENCY VIRUS INFECTION AS A MODEL FOR CNS INFECTION

本研究的目标是进一步完善猫/FIV系统， 慢病毒感染CNS的模型。 我们希望确定 FIV诱导的CNS功能障碍的分子基础，定义细胞 受病毒感染的人群，并调查直接和 病毒作用的间接机制。 我们将分析一个 一系列野生型和突变型FIV，其表现出不同的宿主细胞范围 属性，以评估每个变体的传播程度 病毒在中枢神经系统和外周，以及确定如何宿主细胞 范围特性影响CNS疾病的发病率和严重程度。 待测试的FIV包括分子克隆的亲本FIV-PPR;突变体FIV-PPR。 缺乏功能性脱氧尿苷三磷酸酶（DU）基因的FIV-PPR; FIV-PPR的天然变体，能够有效感染神经胶质细胞， 体外细胞系，以及T细胞和巨噬细胞;分子克隆 FIV-34 TF 10，一种来源于FIV-花瓣属的物种，其缺乏功能性 Orf 2基因;和FIV-034 TF 10的“突变体：“，其中阅读框 已经修复了 这些FIV中的每一个都具有不同的宿主细胞 在体外的表型范围，可能导致独特的作用机制， CNS。 与Fox组件合作，我们将直接使用 体内感染的小胶质细胞的连续传代作为促进 增强FIV-PPR的“亲神经性”，这是一种成功的手术， 为福克斯博士选择SIVmac 251的神经侵入形式。 我们将 还研究了病毒Env糖蛋白对细胞增殖的间接影响， 通过制备全长和截短形式的Env FIV-P蛋白（PR、FIV-PPR神经胶质细胞和FIV-34 TF 10. 这些蛋白质将 在体内Henriksen组件中使用，以评估IC的影响 接种病毒糖蛋白对大鼠睡眠结构的影响， 猫模特 糖蛋白也将用于确定暴露是否 SU将影响小胶质细胞的转录模式， 与Sutcliffe组件合作。 该部分还将 为所有人提供病毒学、免疫学和感染细胞支持 其他组件，包括菲利普斯、福克斯和萨尔维特尼克组件， 以及样本评估核心。 这些研究将进一步促进我们的 慢病毒如何感染和干扰CNS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.