Hepatitis C Drives Neuropathogenesis in HIV/HCV Coinfection Patients

描述(由申请人提供)： 在研究感染艾滋病毒和丙型肝炎病毒的人时，我们发现，与单独感染任何一种病毒的人相比，混合感染(艾滋病毒/丙型肝炎病毒)的人认知功能障碍更大。有大量合并感染的人是丙型肝炎病毒携带者，但通过抗逆转录病毒疗法(ART)有效的病毒抑制，仍将艾滋病毒保持在50拷贝/毫升以下。来自我们实验室的新数据显示，与丙型肝炎病毒或病毒控制的艾滋病毒感染者相比，合并感染的患者患认知障碍的风险更大。我们最近的发现在一些混合感染的人中发现了单核细胞I型干扰素α反应，而病毒抑制的艾滋病毒和丙型肝炎病毒单一感染的人中没有这种反应。重要的是，这种单核细胞激活图谱的特征是6个基因的表达与合并感染患者的认知障碍密切相关。由于HIVUD(未检测到；50拷贝/毫升)在HIV单一感染者和混合感染者中都很常见，单核细胞中的干扰素激活情况可能是由于丙型肝炎病毒，这表明成功的丙型肝炎病毒治疗可能会降低激活并随后改善认知。过去，大多数合并感染的患者没有接受标准的丙型肝炎病毒治疗，因为它的成功率很低，而且经常出现令人虚弱的副作用。然而，新的丙型肝炎病毒蛋白酶抑制剂(PI)联合聚乙二醇干扰素/利巴韦林(三联疗法)是一种更持久地实现持续病毒应答(SVR)的有效治疗方法。我们建议对选择接受治疗的合并感染患者进行研究，并在治疗前后评估他们的单核细胞活化和神经心理表现的变化。我们还建议探索病毒诱导的单核细胞激活对神经细胞功能影响的机制。我们发现，来自联合感染者的单核细胞脱落了含有miRNAs(MiRs)的外切体，这种外切体可以抑制与神经细胞相关靶标相关的必要转录。我们的总体假设是，在合并感染的患者中，通过清除丙型肝炎病毒来降低免疫激活情况将导致认知能力的改善和M/Mφ免疫激活MIR的减少。这项工作的成功完成将验证我们的外周血单核细胞与认知障碍相关的免疫激活标志物，并从机制上说明联合感染如何通过激活的单核细胞衍生的外体miRs对神经细胞功能产生不利影响。

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 IFNα 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/Mφ 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.