Lester Richard T, Yao Xiao-Dan, Ball T Blake, McKinnon Lyle R, Kaul Rupert, Wachihi Charles, Jaoko Walter, Plummer Francis A, Rosenthal Kenneth L
Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada.
AIDS. 2008 Mar 30;22(6):685-94. doi: 10.1097/QAD.0b013e3282f4de35.
Toll-like receptors (TLR) are important in pathogen recognition and may play a role in HIV disease. We evaluated the effect of chronic untreated and treated HIV-1 infection on systemic TLR expression and TLR signalling.
Two hundred HIV-infected and uninfected women from a Kenya cohort participated in the studies. TLR1 to TLR10 messenger RNA expression was determined by quantitative reverse transcriptase polymerase chain reaction in peripheral blood mononuclear cells (PBMC). TLR ligand responsiveness was determined in or using ex-vivo PBMC by cytokine production in culture supernatants.
Chronic, untreated HIV-1 infection was significantly associated with increased mRNA expression of TLR6, TLR7, and TLR8 and when analysis was limited to those with advanced disease (CD4 cell count < 200 cells/ml) TLR2, TLR3, and TLR4 were additionally elevated. TLR expression correlated with the plasma HIV-RNA load, which was significant for TLR6 and TLR7. In vitro HIV single-stranded RNA alone could enhance TLR mRNA expression. PBMC of HIV-infected subjects also demonstrated profoundly increased proinflammatory responsiveness to TLR ligands, suggesting sensitization of TLR signalling in HIV. Finally, viral suppression by HAART was associated with a normalization of TLR levels.
Together, these data indicate that chronic viraemic HIV-1 is associated with increased TLR expression and responsiveness, which may perpetuate innate immune dysfunction and activation that underlies HIV pathogenesis, and thus reveal potential new targets for therapy.
Toll样受体（TLR）在病原体识别中起重要作用，可能在HIV疾病中发挥作用。我们评估了慢性未经治疗和经治疗的HIV-1感染对全身TLR表达和TLR信号传导的影响。
来自肯尼亚队列的200名感染和未感染HIV的女性参与了研究。通过定量逆转录聚合酶链反应测定外周血单核细胞（PBMC）中TLR1至TLR10信使核糖核酸的表达。通过培养上清液中的细胞因子产生，在体外PBMC中或使用体外PBMC测定TLR配体反应性。
慢性未经治疗的HIV-1感染与TLR6、TLR7和TLR8的信使核糖核酸表达增加显著相关，当分析仅限于晚期疾病患者（CD4细胞计数<200个细胞/毫升）时，TLR2、TLR3和TLR4也升高。TLR表达与血浆HIV-RNA载量相关，这在TLR6和TLR7中具有显著性。单独的体外HIV单链核糖核酸可增强TLR信使核糖核酸表达。HIV感染受试者的PBMC对TLR配体的促炎反应性也显著增加，表明HIV中TLR信号传导的致敏。最后，高效抗逆转录病毒治疗（HAART）的病毒抑制与TLR水平的正常化相关。
总之，这些数据表明慢性病毒血症性HIV-1与TLR表达和反应性增加相关，这可能使HIV发病机制所基于的先天性免疫功能障碍和激活持续存在，从而揭示潜在的新治疗靶点。
