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首页> 外文期刊>Journal of neuroinflammation >T-cell reconstitution during murine acquired immunodeficiency syndrome (MAIDS) produces neuroinflammation and mortality in animals harboring opportunistic viral brain infection
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T-cell reconstitution during murine acquired immunodeficiency syndrome (MAIDS) produces neuroinflammation and mortality in animals harboring opportunistic viral brain infection

机译：鼠获得性免疫缺陷综合症（MAIDS）期间的T细胞重建会在带有机会性病毒性脑部感染的动物中引起神经炎症和死亡

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Background Highly active antiretroviral therapy (HAART) restores inflammatory immune responses in AIDS patients which may unmask previous subclinical infections or paradoxically exacerbate symptoms of opportunistic infections. In resource-poor settings, 25% of patients receiving HAART may develop CNS-related immune reconstitution inflammatory syndrome (IRIS). Here we describe a reliable mouse model to study underlying immunopathological mechanisms of CNS-IRIS. Methods Utilizing our HSV brain infection model and mice with MAIDS, we investigated the effect of immune reconstitution on MAIDS mice harboring opportunistic viral brain infection. Using multi-color flow cytometry, we quantitatively measured the cellular infiltrate and microglial activation. Results Infection with the LP-BM5 retroviral mixture was found to confer susceptibility to herpes simplex virus (HSV)-1 brain infection to normally-resistant C57BL/6 mice. Increased susceptibility to brain infection was due to severe immunodeficiency at 8 wks p.i. and a marked increase in programmed death-1 (PD-1) expression on CD4+ and CD8+ T-cells. Both T-cell loss and opportunistic brain infection were associated with high level PD-1 expression because PD-1-knockout mice infected with LP-BM5 did not exhibit lymphopenia and retained resistance to HSV-1. In addition, HSV-infection of MAIDS mice stimulated peripheral immune cell infiltration into the brain and its ensuing microglial activation. Interestingly, while opportunistic herpes virus brain infection of C57BL/6 MAIDS mice was not itself lethal, when T-cell immunity was reconstituted through adoptive transfer of virus-specific CD3+ T-cells, it resulted in significant mortality among recipients. This immune reconstitution-induced mortality was associated with exacerbated neuroinflammation, as determined by MHC class II expression on resident microglia and elevated levels of Th1 cytokines in the brain. Conclusions Taken together, these results indicate development of an immune reconstitution disease within the central nervous system (CNS-IRD). Experimental immune reconstitution disease of the CNS using T-cell repopulation of lymphopenic murine hosts harboring opportunistic brain infections may help elucidate neuroimmunoregulatory networks that produce CNS-IRIS in patients initiating HAART.
机译：背景技术高效抗逆转录病毒疗法（HAART）可恢复AIDS患者的炎症免疫反应，从而掩盖以前的亚临床感染或矛盾地加剧机会性感染的症状。在资源匮乏的环境中，接受HAART的患者中有25％可能会发生中枢神经系统相关的免疫重建炎症综合症（IRIS）。在这里，我们描述了一个可靠的小鼠模型来研究中枢神经系统IRIS的潜在免疫病理机制。方法利用HSV脑感染模型和MAIDS小鼠，研究免疫重建对带有机会性病毒性脑感染的MAIDS小鼠的影响。使用多色流式细胞仪，我们定量测量了细胞浸润和小胶质细胞活化。结果发现，用LP-BM5逆转录病毒混合物感染后，正常抵抗力的C57BL / 6小鼠易患单纯疱疹病毒（HSV）-1脑部感染。对脑部感染的易感性增加是由于在每周第8周出现严重的免疫缺陷。 CD4 +和CD8 + T细胞上的编程死亡1（PD-1）表达显着增加。 T细胞丢失和机会性脑部感染均与高水平的PD-1表达有关，因为被LP-BM5感染的PD-1基因敲除小鼠不表现出淋巴细胞减少症，并保留了对HSV-1的抵抗力。此外，感染MAIDS小鼠的HSV刺激了外周免疫细胞向大脑的浸润及其随后的小胶质细胞活化。有趣的是，虽然C57BL / 6 MAIDS小鼠的机会性疱疹病毒脑部感染本身并不致命，但通过过继转移病毒特异性CD3 + T细胞重新构建T细胞免疫力时，却导致了受体死亡。这种免疫重建诱导的死亡率与神经炎症加重有关，这由驻留小胶质细胞上的MHC II类表达和大脑中Th1细胞因子水平升高确定。结论综上所述，这些结果表明中枢神经系统（CNS-IRD）发生了免疫重建疾病。使用淋巴性鼠宿主的T细胞重新聚集来进行中枢神经系统的实验性免疫重建疾病，该疾病宿主可能存在机会性脑部感染，这可能有助于阐明在启动HAART的患者中产生CNS-IRIS的神经免疫调节网络。

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