Innate immune responses and control of acute simian immunodeficiency virus replication in the central nervous system
Innate immune responses and control of acute simian immunodeficiency virus replication in the central nervous system
复制标题
DOI：
10.1080/13550280490268179
复制
发表时间：
2004-01-01
影响因子：
3.2
通讯作者：
Clements, JE
中科院分区：
文献类型：
--
作者：
Barber, SA;Herbst, DS;Clements, JE
人类免疫缺陷病毒（HIV）和猴免疫缺陷病毒14型（SIV）在急性感染时可侵入中枢神经系统（CNS），但病毒复制明显受到控制，因为HIV/SIV感染者的CNS疾病的临床和病理表现通常在感染后期出现，与免疫抑制和获得性免疫缺陷综合征（AIDS）相一致。使用已建立的HIV痴呆的SIV/猕猴模型，作者最近证明，早在接种后21天（p.i.），急性病毒复制在大脑中下调（至无法检测到的病毒RNA水平），而不是外周。病毒DNA在大脑中的水平保持不变，这表明感染的细胞在CNS中持续存在，并且复制在转录水平上受到很大程度的抑制。在体外，巨噬细胞中HIV的活跃复制可以通过干扰素（IFN）β治疗来抑制，其机制涉及诱导显性阴性形式的转录因子C/EBP（CCAAT/增强子结合蛋白）β。由于巨噬细胞是CNS中感染HIV/SIV的主要细胞类型，并且巨噬细胞中的HIV复制需要病毒长末端重复序列（LTR）内的C/EBP位点，因此作者认为抑制C/EBP依赖性转录有助于抑制CNS中急性HIV/SIV复制的机制。在这里，作者报道了IFN β 3也可以在体外抑制猕猴巨噬细胞中正在进行的SIV复制。此外，作者证明，脑中的IFN β水平在感染后7至21天之间增加。与C/EBP β的显性阴性亚型表达增加平行。这些结果表明，涉及IFN β的先天性免疫应答可能有助于控制CNS中急性SIV复制的机制。
Human immunodeficiency virus (HIV) and simian immunodeficiency virus 14 (SIV) can invade the central nervous system (CNS) during acute infection but virus replication is apparently controlled because clinical and pathological manifestations of CNS disease in HIV/SIV-infected individuals usually present later in infection, coincident with immunosuppression and acquired immunodeficiency syndrome (AIDS). Using an established SIV/macaque model of HIV dementia, the authors recently demonstrated that acute virus replication is down-regulated (to undetectable viral RNA levels) in the brain, but not the periphery, as early as 21 days post inoculation (p.i.). Viral DNA levels in the brain remain constant, suggesting that infected cells persist in the CNS and that replication is inhibited largely at a transcriptional level. In vitro, active replication of HIV in macrophages can be inhibited by treatment with interferon (IFN)beta via a mechanism involving induction of a dominant-negative form of the transcription factor C/EBP (CCAAT/enhancer-binding protein)beta. Because macrophages are the primary cell types infected with HIV/SIV in the CNS and HIV replication in macrophages requires C/EBP sites within the viral long terminal repeat (LTR), the authors considered the possibility that suppression of C/EBP-dependent transcription contributes to the mechanism by which acute HIV/SIV replication is inhibited in the CNS. Here, the authors report that IFN)3 can also inhibit ongoing SIV replication in macaque macrophages in vitro. Further, the authors demonstrate that IFNbeta levels in the brain increase between 7 and 21 days p.i. in parallel with increased expression of the dominant-negative isoform of C/EBPbeta. These results suggest that innate immune responses involving IFNbeta may contribute to the mechanism(s) controlling acute SIV replication in the CNS.