Mamik Manmeet K, Ghorpade Anuja
Department of Cell Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas, United States of America.
PLoS One. 2014 Mar 24;9(3):e92145. doi: 10.1371/journal.pone.0092145. eCollection 2014.
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.
趋化因子CXCL8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，伴随着中枢神经系统中促炎细胞因子如白细胞介素-1β和肿瘤坏死因子-α的增加，是人类免疫缺陷病毒（HIV）-1感染的一个标志。我们之前报道过HIV-1感染与脑组织和人星形胶质细胞中CXCL8的上调有关。趋化因子在白细胞的运输以及HIV-1感染细胞穿过血脑屏障的运输过程中起着关键作用，这在HIV-1中枢神经系统疾病中发挥重要作用。在抗逆转录病毒治疗时代，HIV-1在脑中低水平的有效复制是神经发病机制调控的一个关键组成部分。本研究调查了CXCL8对HIV-1在人单核细胞衍生巨噬细胞（MDM）和原代人小胶质细胞中有效感染的影响。
用血液或脑源性HIV-1分离株HIV-1ADA或HIV-1JRFL感染人MDM和小胶质细胞。用CXCL8处理显著上调了HIV-1感染的MDM和小胶质细胞上清液中的HIV-1 p24水平。此外，作为病毒基因组整合指标的2-长末端重复序列（LTR）环的形成在CXCL8处理的HIV-1感染的MDM和小胶质细胞中显著更高。用HIV-1 LTR荧光素酶报告构建体瞬时转染U-937细胞，在用CXCL8处理时导致启动子活性增加。此外，在CXCL8处理后的HIV-1感染的MDM中观察到核因子-κB的核转位增加。阻断CXCL8受体CXCR1和CXCR2消除了CXCL8介导的HIV-1复制增强。
我们的结果表明，CXCL8通过受体CXCR1和CXCR2介导HIV-1在MDM和小胶质细胞中的有效感染。这些结果表明，CXCL8通过增加核因子-κB向细胞核的转位发挥其下游作用，从而促进HIV-1 LTR活性。
