Proteomic profiling of CSF during SIV infection

描述（由申请人提供）：大约1/4的免疫抑制AIDS患者发生神经退行性疾病，临床特征为HIV相关痴呆综合征（HIVD）。我们推测，HIVD是由于HIV感染的单核细胞进入大脑的运输增加。单核细胞在离开血流并进入CNS时被激活，在CNS中它们转化为巨噬细胞，启动病毒复制和神经炎性级联反应。组织损伤开始了星形胶质细胞和小胶质细胞活化的循环，为进一步的HIV感染提供了易感靶点，并破坏了突触连接。我们建议使用SIV感染的猕猴nemestrina作为一个模型，艾滋病毒脑炎，探讨几个假设与我们的慢病毒神经发病机制的理论。我们的首要假设是：SIV感染的进展导致单核细胞/巨噬细胞感染增加并运输到CNS中，这与CSF中的独特蛋白质组特征相关。具体目标1将使用质谱法比较来自SIV感染的患有和不患有SFV脑炎的猕猴的CSF的蛋白质组谱。我们将检验以下假设：患有脑炎的猕猴的CSF将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特征。特异性目标2将鉴定区分脑炎与非脑炎动物CSF的独特蛋白质峰（生物标志物）。具体目标3将回顾性比较在感染的不同阶段采样的CSF生物标志物组。我们假设在终末感染前1-2个月，CSF中单核细胞进入的蛋白质组学标志物将先于CNS疾病的发展。这些研究将揭示由于SIV感染的单核细胞进入CNS而引起的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.