HIV-1 gp120 signaling through TLR4 modulates innate immune activation in human macrophages and the biology of hepatic stellate cells
HIV-1 gp120 signaling through TLR4 modulates innate immune activation in human macrophages and the biology of hepatic stellate cells
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DOI：
10.1189/jlb.4a1215-534r
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发表时间：
2016-09-01
影响因子：
5.5
通讯作者：
Gessani, Sandra
中科院分区：
文献类型：
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作者：
Del Corno, Manuela;Cappon, Andrea;Gessani, Sandra
人类MDM和HSC中TLR 4和HIV-1 gp 120之间的相互作用，作为慢性免疫激活和肝纤维化进展的新决定因素高效抗逆转录病毒疗法显著改善了艾滋病毒感染者的预后。然而，长期治疗的患者仍然表现出增加的死亡率，并且即使具有不可检测的血浆病毒血症，也经常经历持续的免疫激活。此外，肝脏相关的死亡率现在是接受高效抗逆转录病毒治疗的HIV感染者通过加速纤维化进展导致的非艾滋病相关死亡的最常见原因。TLR是宿主对病原体应答的第一线，通过感受病毒结构蛋白在人类宿主防御病毒中发挥重要作用。越来越多的证据表明TLR 4在慢性免疫激活、HIV识别/复制和肝纤维化进展中起关键作用，这表明HIV触发TLR 4可能决定了多方面的AIDS发病机制的某些方面。在这项研究中，我们提供的证据表明宿主TLR 4和HIV-1 gp 120之间的相互作用，在人类单核细胞衍生的巨噬细胞和肝星状细胞，导致细胞内途径和生物活性，介导促炎症和促纤维化信号。最后，我们假设CCR 5和TLR 4可能是共同受体簇的一部分，因为特异性拮抗剂对CCR 5的阻断损害了巨噬细胞响应LPS产生趋化因子的能力。慢性免疫激活和肝纤维化仍然是高效抗逆转录病毒治疗成功的重要障碍。因此，gp 120-TLR 4轴作为免疫系统和肝星状细胞生物学的新决定因素的鉴定为HIV感染和疾病的管理开辟了新的前景。
Interaction between TLR4 and HIV-1 gp120 in human MDM and HSC, as a novel determinant of chronic immune activation and liver fibrosis progression. Highly active antiretroviral therapy has significantly improved the prognosis of HIV-infected subjects. However, patients treated long term still manifest increased mortality and, even with undetectable plasma viremia, often experience persistent immune activation. Furthermore, liver-related mortality is now the most common cause of non-AIDS-related death in HIV-infected individuals on highly active antiretroviral therapy through accelerated fibrosis progression. TLRs are the first line of the host response to pathogens and play an important role in human host defense against viruses through sensing of viral structural proteins. Growing evidence points to TLR4 as a key player in chronic immune activation, HIV recognition/replication, and liver fibrosis progression, suggesting that HIV triggering of TLR4 may dictate some aspects of the multifaceted AIDS pathogenesis. In this study, we provide evidence for an interplay between host TLR4 and HIV-1 gp120 in human monocyte-derived macrophages and hepatic stellate cells, leading to intracellular pathways and biologic activities that mediate proinflammatory and profibrogenic signals. Finally, we hypothesize that CCR5 and TLR4 are likely part of a common receptor cluster, as the blocking of CCR5 by specific antagonists impairs the macrophage capacity to produce chemokines in response to LPS. Chronic immune activation and liver fibrosis remain important obstacles for highly active antiretroviral therapy success. Thus, the identification of gp120-TLR4 axis as a novel determinant of immune system and hepatic stellate cell biology opens new perspectives to the management of HIV infection and disease.