Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan.
Int Immunol. 2010 Jun;22(6):469-78. doi: 10.1093/intimm/dxq032. Epub 2010 May 26.
In the course of the development of acquired immunodeficiency syndrome (AIDS), bacterial infection causes deleterious effects on the progression of the disease; bacterial LPS in the circulation activate immune cells, resulting in the acceleration of HIV replication. However, the precise HIV activation mechanisms in infected hosts remain largely unknown. Previously, we generated transgenic (Tg) mice carrying the HIV type I (HIV-1) genome and showed that LPS induces the activation of HIV-1 in splenocytes through the induction of tumor necrosis factor (TNF) and IL-1, although similarly induced IFN-gamma and IL-6 are not involved. In this study, we analyzed the mechanisms of HIV-1 activation in macrophages using these HIV-1 Tg mice, because macrophages are one of the major reservoirs of HIV-1. In contrast to splenocytes, direct Toll-like receptor (TLR) 4 signaling rather than TLR-induced pro-inflammatory cytokines was responsible for the LPS-induced activation of HIV-1 in macrophages, because the time course of HIV-1 activation was earlier than that observed in splenocytes and TNF neutralization did not inhibit the activation. p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-kappaB) activation, but neither extracellular signal-regulated kinase nor c-Jun N-terminal kinase activation, were required for the activation, because only inhibitors for p38 MAPK and NF-kappaB suppressed activation of HIV-1. Furthermore, we showed that myeloid differentiation primary response gene (MyD) 88, rather than Toll/IL-1R domain-containing adaptor inducing IFN-beta (TRIF), was required as an adaptor molecule for this activation using Myd88(-/-) mice and Dynasore, a specific inhibitor for TRIF, and small interfering RNAs specific for Myd88 and Trif. These observations suggest that suppression of these molecules, which are involved in the TLR4-MyD88 pathway and the downstream p38 MAPK and NF-kappaB pathways, should be beneficial to prevent development of AIDS in HIV-1-infected people.
在获得性免疫缺陷综合征（AIDS）的发展过程中，细菌感染对疾病的进展产生有害影响；循环中的细菌 LPS 激活免疫细胞，导致 HIV 复制加速。然而，感染宿主中 HIV 的确切激活机制在很大程度上仍然未知。此前，我们生成了携带 HIV 型 I（HIV-1）基因组的转基因（Tg）小鼠，并表明 LPS 通过诱导肿瘤坏死因子（TNF）和白细胞介素-1（IL-1）来激活 HIV-1，尽管类似诱导的 IFN-γ和 IL-6 不参与其中。在这项研究中，我们使用这些 HIV-1 Tg 小鼠分析了巨噬细胞中 HIV-1 的激活机制，因为巨噬细胞是 HIV-1 的主要储存库之一。与脾细胞不同，直接 Toll 样受体（TLR）4 信号而不是 TLR 诱导的促炎细胞因子负责 LPS 诱导的巨噬细胞中 HIV-1 的激活，因为 HIV-1 的激活时间早于在脾细胞中观察到的时间，并且 TNF 中和并未抑制激活。p38 丝裂原活化蛋白激酶（MAPK）和核因子 kappa B（NF-kappaB）的激活，但细胞外信号调节激酶或 c-Jun N-末端激酶的激活都不是必需的，因为只有 p38 MAPK 和 NF-kappaB 的抑制剂抑制了 HIV-1 的激活。此外，我们使用 Myd88(-/-) 小鼠和 Dynasore（一种特异性 TRIF 抑制剂）以及针对 Myd88 和 Trif 的小干扰 RNA 表明，髓样分化初级反应基因（MyD）88，而不是 Toll/IL-1R 域包含衔接子诱导 IFN-beta（TRIF），作为该激活的衔接子分子是必需的。这些观察结果表明，抑制这些参与 TLR4-MyD88 途径及其下游 p38 MAPK 和 NF-kappaB 途径的分子，应该有助于预防 HIV-1 感染者 AIDS 的发展。
