Monocyte/macrophage trafficking in acquired immunodeficiency syndrome encephalitis: lessons from human and nonhuman primate studies.
Monocyte/macrophage trafficking in acquired immunodeficiency syndrome encephalitis: lessons from human and nonhuman primate studies.
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DOI：
10.1080/13550280802132857
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发表时间：
2008-08
影响因子：
3.2
通讯作者：
Rappaport J
中科院分区：
文献类型：
--
作者：
Fischer-Smith T;Bell C;Croul S;Lewis M;Rappaport J
在此，作者讨论了人类和动物模型中关于人类免疫缺陷病毒（HIV）在中枢神经系统（CNS）发病机制的两种相反观点的证据：(1)HIV在中枢神经系统中的感染是一种区隔性感染，病毒感染的巨噬细胞早期进入中枢神经系统，感染驻留的小胶质细胞和星形胶质细胞，并在病程后期达到潜伏期，向暴发性中枢神经系统感染进化；或者，(2)外周发生的事件导致单核细胞/巨噬细胞（MΦ）稳态改变，感染和/或未感染MΦs的中枢神经系统侵袭增加。在这里，作者重新评估了支持后一种模型的证据，讨论了区分正常驻留小胶质细胞与HIV脑炎（HIVE）中积累的小胶质细胞的表型特征。CD163通常在人类和恒河猴正常中枢神经系统的血管周围MΦs表达，而不是驻留小胶质细胞。与其他研究一致，作者证实CD163在HIVE和猿猴免疫缺陷病毒脑炎（SIVE）中通过脑MΦs表达。hiv血清阳性HIVE或hiv相关进行性多灶性白质脑病（PML）患者的中枢神经系统组织也进行了检查。在HIVE中，作者进一步证明了CD163和CD16 （FcγIII受体）基因表达的共定位，后者与体内单核细胞的HIV感染和感染许可性相关。事实上，CD163+ MΦs和小胶质细胞经常在HIVE CNS中被有效感染。在SIV感染的恒河猴中，CD163+细胞在脑炎动物的血管周围、结节病变和实质内积聚。同样，在HIVE中，实质小胶质细胞和血管周围MΦs是CD163+。与HIVE相比，hiv相关PML中的CD163+血管周围和实质MΦs仅与脱髓鞘病变区域相关。有趣的是，感染siv的恒河猴的病毒负荷主要在1 × 106拷贝/ml或更高时发展为脑炎。为了进一步研究CNS中CD163+/CD16+ MΦs/小胶质细胞与外周稳态改变之间的关系，作者对siv感染的恒河猴外周血单个核细胞（PBMCs）进行了流式细胞术分析。结果表明，在可检测到病毒的动物中，CD163+/CD16+单核细胞的百分比频率增加，与病毒负担增加和CD4+ t细胞下降显著相关。这些结果提示单核细胞亚群在HIV/SIV中枢神经系统疾病以及慢病毒感染的免疫发病机制中的重要性。作者进一步讨论了CD163+/CD16+单核细胞/MΦ亚群扩增的潜在作用，改变骨髓稳态，以及免疫极化和抑制的潜在后果。本文的结果和讨论为获得性免疫缺陷综合征（AIDS）疗法和疫苗设计的发展提供了新的途径。
Here the authors discuss evidence in human and animal models supporting two opposing views regarding the pathogenesis of human immunodeficiency virus (HIV) in the central nervous system (CNS): (1) HIV infection in the CNS is a compartmentalized infection, with the virus-infected macrophages entering the CNS early, infecting resident microglia and astrocytes, and achieving a state of latency with evolution toward a fulminant CNS infection late in the course of disease; or alternatively, (2) events in the periphery lead to altered monocyte/macrophage (MΦ) homeostasis, with increased CNS invasion of infected and/or uninfected MΦs. Here the authors have reevaluated evidence presented in the favor of the latter model, with a discussion of phenotypic characteristics distinguishing normal resident microglia with those accumulating in HIV encephalitis (HIVE). CD163 is normally expressed by perivascular MΦs but not resident microglia in normal CNS of humans and rhesus macaques. In agreement with other studies, the authors demonstrate expression of CD163 by brain MΦs in HIVE and simian immunodeficiency virus encephalitis (SIVE). CNS tissues from HIV-sero positive individuals with HIVE or HIV-associated progressive multifocal leukoencephalopathy (PML) were also examined. In HIVE, the authors further demonstrate colocalization of CD163 and CD16 (FcγIII recptor) gene expression, the latter marker associated with HIV infection of monocyte in vivo and permissivity of infection. Indeed, CD163+ MΦs and microglia are often productively infected in HIVE CNS. In SIV infected rhesus macaques, CD163+ cells accumulate perivascularly, within nodular lesions and the parenchyma in animals with encephalitis. Likewise, parenchymal microglia and perivascular MΦs are CD163+ in HIVE. In contrast to HIVE, CD163+perivascular and parenchymal MΦs in HIV-associated PML were only associated with areas of demyelinating lesions. Interestingly, SIV-infected rhesus macaques whose viral burden was predominantly at 1 × 106 copies/ml or greater developed encephalitis. To further investigate the relationship between CD163+/CD16+ MΦs/microglia in the CNS and altered homeostasis in the periphery, the authors performed flow-cytometric analyses of peripheral blood mononuclear cells (PBMCs) from SIV-infected rhesus macaques. The results demonstrate an increase in the percent frequency of CD163+/CD16+ monocytes in animals with detectable virus that correlated significantly with increased viral burden and CD4+ T-cell decline. These results suggest the importance of this monocyte subset in HIV/SIV CNS disease, and also in the immune pathogenesis of lentiviral infection. The authors further discuss the potential role of CD163+/CD16+ monocyte/MΦ subset expansion, altered myeloid homeostasis, and potential consequences for immune polarization and suppression. The results and discussion here suggest new avenues for the development of acquired immunodeficiency syndrome (AIDS) therapeutics and vaccine design.
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