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。以前是急性暴发性病理，在高效抗逆转录病毒治疗（HAART）的时代，它已成为一种慢性更阴险的疾病。感染HIV-1的个体继续发展为神经认知功能障碍，但发生率较低，即使HIV-1相关脑炎是一种持续的死后发现。我们假设，将许多因素综合起来，将HIV-1患者的痴呆症风险概况。我们确定HAD的潜在危险因素为高病毒载量、APOE4基因型、炎性单核细胞/巨噬细胞表型、年龄、趋化因子MCP-1的增加、TNFalpha和CCR5基因的多态性、糖尿病、我们比较了hiv -1感染受试者高病毒载量和低病毒载量的基因表达微阵列，发现一些基因与高病毒载量相关，这些基因也与上述几种危险因素相对应。我们的具体目标是：1)利用基因微阵列、RT-PCR和Western分析进一步研究hiv -1感染个体的单核细胞激活/功能障碍状态，并将其与已知的危险因素联系起来；2)进一步表征HIV-1感染个体特异性差异表达基因或途径的作用；3)确定HIV-1感染单核细胞/巨噬细胞上清液对人脑聚集物的影响，作为体内脑结构和代谢物测量的替代品；4)鉴定hiv -1感染受试者的单核细胞基因表达谱，这些基因表达谱分别与MRI和MRSI测量的特定脑结构和代谢物损伤相关，并将其与其他危险因素联系起来。这些发现将帮助我们开发出具有痴呆风险的hiv -1感染个体的单核细胞谱，以接受预防性治疗，并作为评估有效治疗的标记。

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.