Human gut-associated lymphoid tissues (GALT) play a key role in the acute phase of HIV infection. The propensity of HIV to replicate in these tissues, however, is not fully understood. Access and migration of naive and memory CD4⁺ T cells to these sites is mediated by interactions between integrin α₄β₇, expressed on CD4⁺ T cells, and MAdCAM, expressed on high endothelial venules. We report here that MAdCAM delivers a potent costimulatory signal to naive and memory CD4⁺ T cells following ligation with α₄β₇. Such costimulation promotes high levels of HIV replication. An anti-α₄β₇ mAb that prevents mucosal transmission of SIV blocks MAdCAM signaling through α₄β₇ and MAdCAM-dependent viral replication. MAdCAM costimulation of memory CD4⁺ T cells is sufficient to drive cellular proliferation and the upregulation of CCR5, while naive CD4⁺ T cells require both MAdCAM and retinoic acid to achieve the same response. The pairing of MAdCAM and retinoic acid is unique to the GALT, leading us to propose that HIV replication in these sites is facilitated by MAdCAM-α₄β₇ interactions. Moreover, complete inhibition of MAdCAM signaling by an anti-α₄β₇ mAb, an analog of the clinically approved therapeutic vedolizumab, highlights the potential of such agents to control acute HIV infection.

中文翻译：

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MAdCAM 通过 Integrin-α4β7 共刺激促进 HIV 复制。


人类肠道相关淋巴组织 (GALT) 在 HIV 感染的急性期发挥着关键作用。然而，艾滋病毒在这些组织中复制的倾向尚不完全清楚。幼稚和记忆 CD4 ⁺ T 细胞对这些位点的访问和迁移是由 CD4 ⁺ T 细胞上表达的整合素 α ₄ β ₇和高内皮小静脉上表达的 MAdCAM 之间的相互作用介导的。我们在此报告，MAdCAM 在与 α ₄ β ₇连接后向幼稚和记忆 CD4 ⁺ T 细胞传递有效的共刺激信号。这种共刺激促进了艾滋病毒的高水平复制。一种抗 α ₄ β ₇ mAb 可防止 SIV 粘膜传播，通过 α ₄ β ₇和 MAdCAM 依赖性病毒复制阻断 MAdCAM 信号传导。 MAdCAM 对记忆 CD4 ⁺ T 细胞的共刺激足以驱动细胞增殖和 CCR5 的上调，而幼稚 CD4 ⁺ T 细胞需要 MAdCAM 和视黄酸才能实现相同的反应。 MAdCAM 和视黄酸的配对是 GALT 所独有的，因此我们推测这些位点中的 HIV 复制是通过 MAdCAM-α ₄ β ₇相互作用促进的。此外，抗α ₄ β ₇ mAb（临床批准的治疗性维多珠单抗的类似物）完全抑制MAdCAM信号传导，凸显了此类药物控制急性HIV感染的潜力。