Chemokine CXCL8 promotes HIV-1 replication in human monocyte-derived macrophages and primary microglia via nuclear factor-κB pathway.
Chemokine CXCL8 promotes HIV-1 replication in human monocyte-derived macrophages and primary microglia via nuclear factor-κB pathway.
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DOI：
10.1371/journal.pone.0092145
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Ghorpade A
中科院分区：
文献类型：
--
作者：
Mamik MK;Ghorpade A
趋化因子CXCL 8是一种重要的中性粒细胞趋化因子，与多种神经退行性疾病有关。细胞因子/趋化因子失衡，伴随中枢神经系统内促炎细胞因子如白细胞介素-1 β和肿瘤坏死因子-α的增加，是人类免疫缺陷病毒（HIV）-1感染的标志。我们先前报道HIV-1感染与脑组织和人类星形胶质细胞中CXCL 8的上调有关。趋化因子在白细胞的运输中起着至关重要的作用，HIV-1感染者通过血脑屏障的运输在HIV-1中枢神经系统疾病中起着重要作用。在后抗逆转录病毒治疗时代，HIV-1在脑内的低水平生产性复制是神经发病机制调节的关键组成部分。本研究调查了CXCL 8对人类单核细胞衍生的巨噬细胞（MDM）和原代人类小胶质细胞中HIV-1的生产性感染的影响。用血液或脑来源的HIV-1分离株、HIV-1ADA或HIV-1 JRFL感染人MDM和小胶质细胞。用CXCL 8处理显著上调HIV-1感染的MDM以及小胶质细胞的上清液中的HIV-1 p24水平。此外，在CXCL 8处理的、HIV-1感染的MDM和小胶质细胞中，2-长末端重复序列（LTR）环的形成（病毒基因组整合的一种量度）显著更高。瞬时转染U937细胞与HIV-1 LTR荧光素酶报告构建体导致增加启动子活性时，用CXCL 8处理。此外，在CXCL 8治疗后，在HIV-1感染的MDM中观察到核因子-κB的核转位增加。阻断CXCL 8受体CXCR 1和CXCR 2可消除CXCL 8介导的HIV-1复制增强。我们的研究结果表明，CXCL 8介导的生产性感染的HIV-1在MDM和小胶质细胞通过受体CXCR 1和CXCR 2。这些结果表明，CXCL 8通过增加核因子-κB向细胞核的移位发挥其下游作用，从而促进HIV-1 LTR活性。
Chemokine CXCL8 is an important neutrophil chemoattractant implicated in various neurodegenerative disorders. Cytokine/chemokine imbalance, with an increase in proinflammatory cytokines like interleukin-1β and tumor necrosis factor-α within the central nervous system, is a hallmark of human immunodeficiency virus (HIV)-1 infection. We previously reported that HIV-1 infection is linked to upregulation of CXCL8 in brain tissues and human astrocytes. Chemokines play crucial roles in trafficking of leukocytes and trafficking of HIV-1-infected across the blood-brain barrier play an important role in HIV-1 central nervous system disease. In the post-antiretroviral therapy era, low level of productive replication of HIV-1 in brain is a critical component of neuropathogenesis regulation. The present study investigated the effect of CXCL8 on productive infection of HIV-1 in human monocytes-derived macrophages (MDM) and primary human microglia. Human MDM and microglia were infected with the blood or brain derived HIV-1 isolates, HIV-1ADA or HIV-1JRFL. Treatment with CXCL8 significantly upregulated HIV-1p24 levels in supernatants of both HIV-1-infected MDM as well as microglia. In addition, the formation of 2-long terminal repeat (LTR) circles, a measure of viral genome integration, was significantly higher in CXCL8-treated, HIV-1-infected MDM and microglia. Transient transfection of U937 cells with HIV-1 LTR luciferase reporter construct resulted in increased promoter activity when treated with CXCL8. Moreover, increased nuclear translocation of nuclear factor-κB was seen in HIV-1-infected MDM following CXCL8 treatment. Blocking CXCL8 receptors CXCR1 and CXCR2 abrogated the CXCL8-mediated enhanced HIV-1 replication. Our results show that CXCL8 mediates productive infection of HIV-1 in MDM and microglia via receptors CXCR1 and CXCR2. These results demonstrate that CXCL8 exerts its downstream effects by increasing translocation of nuclear factor-κB into the nucleus, thereby promoting HIV-1 LTR activity.
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