Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5535, F-34293 Montpellier Cedex 5, France.
Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2549-54. doi: 10.1073/pnas.1121427109. Epub 2012 Jan 30.
Cell cycle entry is commonly considered to positively regulate HIV-1 infection of CD4 T cells, raising the question as to how quiescent lymphocytes, representing a large portion of the viral reservoir, are infected in vivo. Factors such as the homeostatic cytokine IL-7 have been shown to render quiescent T cells permissive to HIV-1 infection, presumably by transiently stimulating their entry into the cell cycle. However, we show here that at physiological oxygen (O(2)) levels (2-5% O(2) tension in lymphoid organs), IL-7 stimulation generates an environment permissive to HIV-1 infection, despite a significantly attenuated level of cell cycle entry. We identify the IL-7-induced increase in Glut1 expression, resulting in augmented glucose uptake, as a key factor in rendering these T lymphocytes susceptible to HIV-1 infection. HIV-1 infection of human T cells is abrogated either by impairment of Glut1 signal transduction or by siRNA-mediated Glut1 down-regulation. Consistent with this, we show that the susceptibility of human thymocyte subsets to HIV-1 infection correlates with Glut1 expression; single-round infection is markedly higher in the Glut1-expressing double-positive thymocyte population than in any of the Glut1-negative subsets. Thus, our studies reveal the Glut1-mediated metabolic pathway as a critical regulator of HIV-1 infection in human CD4 T cells and thymocytes.
细胞周期进入通常被认为正向调节 CD4 T 细胞中的 HIV-1 感染，这就提出了一个问题，即体内如何感染大量病毒储存库代表的静止淋巴细胞。已显示，诸如稳态细胞因子 IL-7 等因素可使静止 T 细胞对 HIV-1 感染具有易感性，可能通过短暂地刺激其进入细胞周期来实现。然而，我们在这里表明，在生理氧（O2）水平（淋巴器官中 2-5%的 O2 张力）下，尽管细胞周期进入水平显著降低，IL-7 刺激仍会产生有利于 HIV-1 感染的环境。我们确定了 IL-7 诱导的 Glut1 表达增加，导致葡萄糖摄取增加，这是使这些 T 淋巴细胞易受 HIV-1 感染的关键因素。通过破坏 Glut1 信号转导或通过 siRNA 介导的 Glut1 下调，可阻断 HIV-1 感染人 T 细胞。与此一致，我们表明人类胸腺细胞亚群对 HIV-1 感染的易感性与 Glut1 表达相关；在表达 Glut1 的双阳性胸腺细胞群体中单轮感染明显高于任何 Glut1 阴性亚群。因此，我们的研究揭示了 Glut1 介导的代谢途径作为人 CD4 T 细胞和胸腺细胞中 HIV-1 感染的关键调节剂。
