Predicting HAD using Monocyte Profiling and Neuroimaging

描述（由申请人提供）：HIV-1相关痴呆（HAD）是一种不断发展的神经系统疾病。以前是一种急性暴发性疾病，在高效抗逆转录病毒治疗（HAART）时代，它已成为一种慢性更隐蔽的疾病。感染HIV-1的个体继续发展神经认知功能障碍，但发生率较低，尽管HIV-1相关脑炎是一种持续的死后发现。我们假设，将有一些因素综合在一起，将个人与艾滋病毒-1在痴呆症的风险。我们确定了HAD的潜在危险因素为高病毒载量、APOE 4基因型、炎性单核细胞/巨噬细胞表型、年龄、趋化因子MCP-1增加、TNF α和CCR 5基因多态性、糖尿病，神经元标记物NAA减少，含胆碱代谢物和肌醇增加。研究人员发现，高病毒载量和低病毒载量的感染受试者中，有几个基因与高病毒载量相关，这也与上述几个风险因素相对应。我们的具体目标是：1）使用基因微阵列、RT-PCR和Western分析进一步研究HIV-1感染个体中单核细胞活化/功能障碍的状态，并将其与已知的风险因素联系起来; 2）进一步表征HIV-1感染个体中特异性差异表达基因或途径的作用; 3）确定HIV-1感染的单核细胞/巨噬细胞上清液对人脑聚集体的影响，作为脑结构和代谢物的体内测量的替代物;和4）鉴定来自HIV-1感染受试者的单核细胞基因表达谱，其与分别通过MRI和MRSI测量的特定脑结构和代谢物的损伤相关，以将这些与其它危险因素相关联。这些发现将帮助我们为有痴呆风险的HIV-1感染者开发单核细胞谱，以接受预防性治疗，并作为评估有效治疗的标志物。

DESCRIPTION (provided by applicant): HIV-1-associated dementia (HAD) is an evolving neurological disorder. Previously an acute fulminate pathology, in the era of highly active antiretroviral therapy (HAART), it has become a chronic more insidious disorder. Individuals infected with HIV-1 continue to develop neurocognitive dysfunction but at lower rates, even though HIV-1-associated encephalitis is a persistent postmortem finding. We hypothesize that there will be a number of factors that taken together will profile individuals with HIV-1 at risk for dementia. We identify the potential risk factors for HAD as a high viral load, an APOE4 genotype, an inflammatory monocyte/macrophage phenotype, age, an increase in the chemokine MCP-1, polymorphisms in the TNFalpha and CCR5 genes, diabetes, a decrease in the neuronal marker NAA and increases in choline-containing metabolites and myo-inositol by MRS. We have compared gene expression microarrays on HIV-1-infected subjects with high and low viral loads and found that several genes are associated with high viral load that also correspond with several risk factors mentioned above. Our specific aims are: 1) To further develop the state of monocyte activation/dysfunction in HIV-1-infected individuals using gene microarrays, RT-PCR and Western analyses and link this to known risk factors; 2) to further characterize the role of specific differentially expressed genes or pathways from individuals with HIV-1 infection; 3) To determine the effect of HIV-1 infected monocyte/macrophage supernatants on human brain aggregates as surrogates for in vivo measures of brain structure and metabolites; and 4) to identify a monocyte gene expression profile from HIV-1-infected subjects that correlates with injury to specific brain structures and metabolites measured by MRI and MRSI, respectively, to correlate these with other risk factors. These findings will help us develop a monocyte profile for HIV-1-infected individuals at risk for dementia to receive preventive therapy as well as serve as markers to assess effective therapies.