Integrin α₄β_7, a CD4 independent receptor of human immunodeficiency virus-1 (HIV-1) gp120, defines a subset of CD4⁺T cells preferentially targeted by HIV. It is also considered as a promising therapeutic target for HIV-1 infection. Despite its role in HIV acquisition and disease progression, HIV-1-mediated integrin α₄β₇ signaling has not been elucidated so far. In view of this, we determined phosphoproteomic signatures of HIV-1 gp120 signaling as well as signaling mediated by the integrin α₄β₇ ligand, mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1), in primary CD4⁺ T cells. This is the first comprehensive report on MAdCAM-1 signaling, which is believed to enhance HIV-1 replication. Importantly, we identified proteins associated with both classical and nonclassical integrin functions. We observed that HIV-1 gp120 signaling is associated with proteins that have previously not been associated with HIV-1 pathogenesis and thus, need to be explored further. There was a significant overlap in proteins identified by both MAdCAM-1 and HIV-1 gp120 signaling, which most likely represents cellular processes triggered upon interaction of HIV-1 gp120 with integrin α₄β_7. Pathway analysis revealed enrichment of processes that could facilitate viral replication as well as viral entry through endocytosis. Although these results warrant independent replication and further validation, they suggest the presence of additional potential therapeutic targets. These results also suggest that combinatorial approaches for targeting both HIV-1 gp120 and MAdCAM-1 signaling may be necessary for efficient control of HIV-1 infection as well as novel innovation strategies in HIV therapeutics.

中文翻译：

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整合蛋白α4β7信号转导在人类免疫缺陷病毒-1发病机理和原代CD4 + T细胞中病毒进入中的作用，如磷酸化蛋白质组学特征所揭示。

整合素α ₄ β _7，人免疫缺陷病毒-1（HIV-1）的gp120的CD4受体独立，定义了CD4的子集⁺ T细胞被HIV优先靶向。它还被认为是HIV-1感染的有希望的治疗靶标。尽管其在HIV感染和疾病进展的作用，HIV-1介导的整合素α ₄ β ₇信令尚未到目前为止阐明。鉴于此，我们确定HIV-1的gp120信号的磷酸化蛋白质组学签名以及通过整合素α介导的信号₄ β ₇配体，粘膜血管地址素细胞粘附分子-1（MAdCAM-1的1）中，在原代CD4 ⁺T细胞。这是关于MAdCAM-1信号传导的第一份综合报告，据信它可增强HIV-1复制。重要的是，我们鉴定了与经典和非经典整合素功能相关的蛋白质。我们观察到，HIV-1 gp120信号传导与以前与HIV-1发病机理不相关的蛋白质有关，因此需要进一步探讨。有在通过的MAdCAM-1和HIV-1的gp120信令两者鉴定的蛋白质一显著的重叠，其中最有可能表示在的相互作用触发的细胞过程的HIV-1的gp120与整合素α ₄ β _7。途径分析表明，丰富的过程可以促进病毒复制以及通过胞吞作用进入病毒。尽管这些结果值得独立复制和进一步验证，但它们表明存在其他潜在的治疗靶标。这些结果还表明，针对HIV-1 gp120和MAdCAM-1信号传导的组合方法对于有效控制HIV-1感染以及HIV治疗中的新创新策略可能是必需的。