Hepatitis C Drives Neuropathogenesis in HIV/HCV Coinfection Patients

描述（由申请人提供）： 当研究感染HIV和HCV的个体时，我们发现合并感染（HIV/HCV）的个体比单独感染任何一种病毒的个体认知功能障碍更大。有大量的合并感染者是HCV病毒血症，但通过抗逆转录病毒治疗（ART）的有效病毒抑制将HIV维持在50拷贝/ml以下。来自我们实验室的新数据显示，合并感染的患者比HCV或病毒控制的HIV感染者有更大的认知障碍风险。我们最近的研究发现，单核细胞I型干扰素？？在一些合并感染的个体中，这种反应在病毒抑制的HIV和HCV单一感染的个体中均不存在。重要的是，这种单核细胞激活特征在于与合并感染个体中的认知障碍强烈相关的6个基因的表达。自艾滋病毒/艾滋病（未发现;<50拷贝/ml）是HIV单感染者和合并感染者的常见情况，单核细胞中的IFN活化谱可能是由于HCV，这表明成功的HCV治疗可能降低活化并随后改善认知。在过去，大多数合并感染的受试者没有接受标准HCV治疗，因为其成功率低，而且经常出现使人衰弱的副作用。然而，新的HCV蛋白酶抑制剂（PI）联合聚乙二醇干扰素/利巴韦林（三联疗法）是一种有效的治疗方法，更一致地实现持续病毒应答（SVR）。我们建议研究选择接受治疗的合并感染受试者，并在治疗前后评估单核细胞活化和神经心理学表现的变化。我们还提出了一个机制的方法，为病毒诱导的单核细胞激活神经细胞功能。我们发现，来自合并感染受试者的单核细胞脱落含有miRNA（miR）的外泌体，这些外泌体可以抑制与神经细胞相关靶点相关的必需转录物。我们的总体假设是，在合并感染的个体中通过治疗清除HCV来降低免疫激活特征将导致认知改善和M/M？免疫激活miR。这项工作的成功完成将验证我们的外周单核细胞标志物的免疫激活的共感染，与认知障碍相关，并机械地显示共感染如何通过激活的单核细胞衍生的外泌体miR不利地影响神经细胞功能。

DESCRIPTION (provided by applicant): When studying individuals who are infected with HIV and HCV, we found greater cognitive dysfunction in those who were coinfected (HIV/HCV) than in individuals with either viral infection alone. There is a large population of coinfected individuals who are HCV viremic and yet maintain HIV below 50 copies/ml through effective viral suppression with antiretroviral therapy (ART). New data from our laboratory show that coinfected patients are at greater risk for cognitive impairment than either HCV or viral controlled HIV- infected subjects. Our recent findings identified a monocyte type I IFN??response in some coinfected individuals that was absent in both virally suppressed HIV and HCV monoinfected individuals. Importantly, this monocyte activation profile was characterized by the expression of 6 genes that strongly correlated with cognitive impairment in coinfected individuals. Since HIVUD (undetected; <50 copies/ml) was common to both HIV mono- and coinfected individuals, the IFN activation profile in the monocytes was likely due to HCV, suggesting that successful HCV treatment might lower activation and subsequently improve cognition. In the past, the majority of coinfected subjects were not treated with standard HCV therapy due to its low success rate and frequent debilitating side effects. However, new HCV protease inhibitors (PIs) combined with peginterferon/ ribavirin (triple therapy) are an effective treatment that more consistently achieves sustained viral response (SVR). We propose to study coinfected subjects who choose to be treated and evaluate them before and after therapy for monocyte activation and changes in neuropsychological performance. We also propose to explore a mechanistic approach for the viral-induced monocyte activation on neural cell function. We show that monocytes from coinfected subjects shed exosomes containing miRNAs (miRs) that can suppress essential transcripts associated with neural cell-related targets. Our overall hypothesis is that reducing th immune activation profile by clearing HCV with treatment in coinfected individuals will result in cognitive improvement and a decrease in M/M? immune-activating miRs. Successful completion of this work will validate our peripheral monocyte markers of immune activation in coinfection that correlate with cognitive impairment plus mechanistically show how coinfection adversely affects neural cell function through activated monocyte-derived exosomal miRs.