Contrasting Roles for TLR Ligands in HIV-1 Pathogenesis
Contrasting Roles for TLR Ligands in HIV-1 Pathogenesis
复制标题
DOI：
10.1371/journal.pone.0012831
复制
发表时间：
2010-09-20
期刊：
影响因子：
3.7
通讯作者：
Margolis, Leonid
中科院分区：
文献类型：
--
作者：
Brichacek, Beda;Vanpouille, Christophe;Margolis, Leonid
宿主对各种病原体的反应的第一条线是由它们与细胞模式识别受体(PRR)的接触触发的。微生物配体与这些受体的结合导致多种细胞因子的诱导，这些因子改变了细胞内和细胞外的环境，直接或间接地干扰了触发病原体的生命周期。这样的变化也可能影响到任何合并感染的微生物。利用Toll样受体(TLRs)5和9的配体，我们检测了它们对人类免疫缺陷病毒(HIV)-1在体外淋巴组织中复制的影响。我们发现这种治疗的结果有显著差异。鞭毛蛋白(TLR5激动剂)可促进趋化CC趋化因子受体5(CCR5)和趋化CXC趋化因子受体4(CXCR4)的HIV-1复制，而寡脱氧核苷酸(ODN)M362(TLR9激动剂)可抑制这两种病毒变体。这些TLR配体对HIV-1复制的不同作用与经配体处理的HIV-1感染组织中CC趋化因子CCL3、CCL4、CCL5以及CXC趋化因子CXCL10和CXCL12的产生的变化有关。这些变化的性质和/或程度取决于配体和HIV-1病毒株。此外，根据分化标志物(CD)25、CD38、CD39、CD69、CD154和人类白细胞抗原D相关(HLA)-DR以及细胞增殖标志物Ki67和CCR5的表达情况，所测试的配体在诱导细胞激活方面的能力不同。在体外处理的淋巴组织中，没有观察到配体处理对细胞凋亡和细胞死亡/丢失的显著影响。我们的结果表明，微生物配体与TLRs的结合是调节混合感染微生物与人类组织中HIV-1相互作用的机制之一。因此，微生物分子或其模拟物与适当的TLRs结合可能成为艾滋病毒治疗或预防的新策略。
The first line of a host's response to various pathogens is triggered by their engagement of cellular pattern recognition receptors (PRRs). Binding of microbial ligands to these receptors leads to the induction of a variety of cellular factors that alter intracellular and extracellular environment and interfere directly or indirectly with the life cycle of the triggering pathogen. Such changes may also affect any coinfecting microbe. Using ligands to Toll-like receptors (TLRs) 5 and 9, we examined their effect on human immunodeficiency virus (HIV)-1 replication in lymphoid tissue ex vivo. We found marked differences in the outcomes of such treatment. While flagellin (TLR5 agonist) treatment enhanced replication of CC chemokine receptor 5 (CCR 5)-tropic and CXC chemokine receptor 4 (CXCR4)-tropic HIV-1, treatment with oligodeoxynucleotide (ODN) M362 (TLR9 agonist) suppressed both viral variants. The differential effects of these TLR ligands on HIV-1 replication correlated with changes in production of CC chemokines CCL3, CCL4, CCL5, and of CXC chemokines CXCL10, and CXCL12 in the ligand-treated HIV-1-infected tissues. The nature and/or magnitude of these changes were dependent on the ligand as well as on the HIV-1 viral strain. Moreover, the tested ligands differed in their ability to induce cellular activation as evaluated by the expression of the cluster of differentiation markers (CD) 25, CD38, CD39, CD69, CD154, and human leukocyte antigen D related (HLA)-DR as well as of a cell proliferation marker, Ki67, and of CCR5. No significant effect of the ligand treatment was observed on apoptosis and cell death/loss in the treated lymphoid tissue ex vivo. Our results suggest that binding of microbial ligands to TLRs is one of the mechanisms that mediate interactions between coinfected microbes and HIV-1 in human tissues. Thus, the engagement of appropriate TLRs by microbial molecules or their mimetic might become a new strategy for HIV therapy or prevention.