Engagement of the CD4 receptor affects the redistribution of Lck to the immunological synapse in primary T cells: implications for T-cell activation during human immunodeficiency virus type 1 infection.
Engagement of the CD4 receptor affects the redistribution of Lck to the immunological synapse in primary T cells: implications for T-cell activation during human immunodeficiency virus type 1 infection.
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CD4 受体的参与影响 Lck 到原代 T 细胞免疫突触的重新分配：对人类免疫缺陷病毒 1 型感染期间 T 细胞激活的影响。
DOI：
10.1128/jvi.01023-08
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发表时间：
2009
影响因子：
5.4
通讯作者：
Chougnet,ClaireA
中科院分区：
文献类型：
--
作者：
Nyakeriga,AliceM;Fichtenbaum,CarlJ;Goebel,Jens;Nicolaou,StellaA;Conforti,Laura;Chougnet,ClaireA
了解人类免疫缺陷病毒1型（HIV-1）感染中免疫反应失调的分子机制对于控制HIV/AIDS至关重要。尽管假设HIV包膜糖蛋白gp 120-CD 4相互作用导致T细胞应答受损，但这种关联的确切机制尚不清楚。为了解决这个问题，我们分析了Lck和F-actin重新分配到免疫突触刺激的人原代CD 4 +T细胞从HIV-1感染的捐助者。用来自HIV未感染供体的CD 4 +T细胞进行类似的实验，所述供体暴露于抗CD 4结构域1抗体，作为gp 120-CD 4相互作用的体外模型，或在刺激前暴露于醛硫醇灭活的HIV-1病毒体。HIV感染患者的CD 4 +T细胞与未感染供体的细胞相比，对Lck和F-actin向突触中的募集表现出2 - 3倍的抑制作用。有趣的是，Lck的募集缺陷在抑制性高效抗逆转录病毒治疗后得到改善。在抗CD 3/CD 28刺激之前，来自未感染HIV的供体的T细胞上的CD 4受体的接合导致类似的缺陷。此外，Lck进入脂筏的再分配被CD 4预接合废除。我们的研究结果表明，在T细胞受体刺激之前，HIV gp 120对CD 4的参与导致早期信号传导事件的失调，因此可能在CD 4 + T细胞功能受损中发挥重要作用。
Understanding the molecular mechanisms underlying dysregulated immune responses in human immunodeficiency virus type 1 (HIV-1) infection is crucial for the control of HIV/AIDS. Despite the postulate that HIV envelope glycoprotein gp120-CD4 interactions lead to impaired T-cell responses, the precise mechanisms underlying such association are not clear. To address this, we analyzed Lck and F-actin redistribution into the immunological synapse in stimulated human primary CD4+T cells from HIV-1-infected donors. Similar experiments were performed with CD4+T cells from HIV-uninfected donors, which were exposed to anti-CD4 domain 1 antibodies, as an in vitro model of gp120-CD4 interactions, or aldithriol-inactivated HIV-1 virions before stimulation. CD4+T cells from HIV-infected patients exhibited a two- to threefold inhibition of both Lck and F-actin recruitment into the synapse, compared to cells from uninfected donors. Interestingly, defective recruitment of Lck was ameliorated following suppressive highly active antiretroviral therapy. Engagement of the CD4 receptor on T cells from HIV-uninfected donors before anti-CD3/CD28 stimulation led to similar defects. Furthermore, the redistribution of Lck into lipid rafts was abrogated by CD4 preengagement. Our results suggest that the engagement of CD4 by HIV gp120 prior to T-cell receptor stimulation leads to dysregulation of early signaling events and could consequently play an important role in impaired CD4+T-cell function.