Proteomic profiling of CSF during SIV infection

描述（由申请人提供）：大约四分之一的免疫抑制艾滋病患者发展为神经退行性疾病，临床特征为HIV相关痴呆复合体（HIVD）。我们推测，hiv是由于被hiv感染的单核细胞进入大脑的贩运增加。单核细胞在离开血流进入中枢神经系统时被激活，在那里它们转化为巨噬细胞，启动病毒复制和神经炎症级联反应。组织损伤开始星形细胞和小胶质细胞激活周期，为进一步的HIV感染提供易感靶点，并破坏突触连通性。我们建议用猴免疫缺陷病毒感染猕猴作为HIV脑炎的模型来探索与我们的慢病毒神经发病理论相关的几个假设。我们的总体假设是：SIV感染的进展导致单核细胞/巨噬细胞感染增加，并与CSF中独特的蛋白质组学特征相关。特异性目的1将使用质谱法比较SIV感染和未感染SFV脑炎的猕猴脑脊液的蛋白质组学特征。我们将验证脑炎猕猴脑脊液具有反映巨噬细胞运输和病毒产生增加的特征性蛋白质组学特征的假设。特异性目标2将鉴定独特的蛋白峰（生物标志物），以区分脑脊液与脑脊液动物。特异性目标3将回顾性比较在不同感染阶段取样的脑脊液生物标志物面板。我们假设在终末期感染前1-2个月，单核细胞侵入的脑脊液蛋白质组学标志物将先于中枢神经系统疾病的发展。这些研究将揭示由于SIV感染的单核细胞进入中枢神经系统而导致脑炎的新生物标志物。

DESCRIPTION (provided by applicant): Approximately 1 in 4 immunosuppressed AIDS patients develop a neurodegenerative disorder clinically characterized as HIV associated dementia complex (HIVD). We theorize that HIVD is due to increased trafficking of HIV-infected monocytes into the brain. Monocytes are activated upon leaving the blood stream and entering the CNS where they transform into macrophages, initiate viral replication and a neuroinflammatory cascade. Tissue damage begins a cycle of astrocytic and microglial activation, providing susceptible targets for further HIV infection and disrupting synaptic connectivity. We propose to use SIV infection of Macaca nemestrina as a model of HIV encephalitis to explore several hypotheses related to our theory of lentiviral neuropathogenesis. Our overarching hypothesis is: Progression of SIV infection leads to increased monocyte/macrophage infection and trafficking into the CNS that is associated with a unique proteomic signature in the CSF. Specific Aim 1 will compare the proteomic profile of CSF from SIV infected macaques with and without SFV encephalitis using mass spectrometry. We will test the hypothesis that CSF from macaques with encephalitis will have a characteristic proteomic signature reflecting increased macrophage trafficking and viral production. Specific Aim 2 will identify the unique protein peaks (biomarkers) that distinguish CSF from encephalitic versus non-encephalitic animals. Specific Aim 3 will retrospectively compare the CSF biomarker panel sampled at different stages of infection. We hypothesize that 1-2 months prior to terminal infection, CSF proteomic markers of monocyte ingress will antedate the development of CNS disease. These studies will uncover novel biomarkers of encephalitis due to trafficking of SIV infected monocytes into the CNS.