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首页> 外文期刊>Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society >The induction of Toll-like receptor tolerance enhances rather than suppresses HIV-1 gene expression in transgenic mice.
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The induction of Toll-like receptor tolerance enhances rather than suppresses HIV-1 gene expression in transgenic mice.

机译：Toll样受体耐受性的诱导增强而不是抑制转基因小鼠中的HIV-1基因表达。

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Microbial-induced proinflammatory pathways are thought to play a key role in the activation of human immunodeficiency virus type 1 (HIV-1) gene expression. The induction of Toll-like receptor (TLR) tolerance leads to a complex reprogramming in the pattern of inflammatory gene expression and down-modulates tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1, and IL-6 production. Using transgenic (Tg) mice that incorporate the entire HIV-1 genome, including the long-terminal repeat, we have previously demonstrated that a number of different TLR ligands induce HIV-1 gene expression in cultured splenocytes as well as purified antigen-presenting cell populations. Here, we have used this model to determine the effect of TLR-mediated tolerance as an approach to inhibiting microbial-induced viral gene expression in vivo. Unexpectedly, Tg splenocytes and macrophages, rendered tolerant in vitro to TLR2, TLR4, and TLR9 ligands as assessed by proinflammatory cytokine secretion and nuclear factor-kappaB activation, showed enhanced HIV-1 p24 production. A similar enhancement was observed in splenocytes tolerized and then challenged with heterologous TLR ligands. Moreover, TLR2- and TLR4-homotolerized mice demonstrated significantly increased plasma p24 production in vivo despite lower levels of TNF-alpha. Together, these results demonstrate that HIV-1 expression is enhanced in TLR-reprogrammed host cells, possibly reflecting a mechanism used by the virus to escape the effects of microbial-induced tolerance during natural infection in vivo.
机译：微生物诱导的促炎途径被认为在人类免疫缺陷病毒1型（HIV-1）基因表达的激活中起关键作用。 Toll样受体（TLR）耐受性的诱导导致炎症基因表达模式的复杂重编程，并下调肿瘤坏死因子α（TNF-alpha），白介素（IL）-1和IL-6的产生。使用整合了整个HIV-1基因组（包括长末端重复序列）的转基因（Tg）小鼠，我们先前已经证明，许多不同的TLR配体在培养的脾细胞以及纯化的抗原呈递细胞中诱导HIV-1基因表达人口。在这里，我们已使用此模型来确定TLR介导的耐受性的作用，作为一种在体内抑制微生物诱导的病毒基因表达的方法。出乎意料的是，通过促炎性细胞因子分泌和核因子-kappaB活化评估，体外对TLR2，TLR4和TLR9配体具有耐受性的Tg脾细胞和巨噬细胞显示出增强的HIV-1 p24产生。在耐受的脾细胞中观察到类似的增强，然后用异源TLR配体攻击。此外，尽管TNF-α的水平较低，但TLR2和TLR4均等化小鼠的体内血浆p24产量显着增加。总之，这些结果表明，HIV-1表达在TLR重新编程的宿主细胞中得到了增强，这可能反映了该病毒在体内自然感染过程中逃脱了微生物诱导的耐受性的机制。

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