The HIV co-receptors, CCR5 and CXCR4, are necessary for HIV entry into target cells, interacting with the HIV envelope protein, gp120, to initiate several signaling cascades thought to be important to the entry process. Co-receptor signaling may also promote the development of neuroHIV by contributing to both persistent neuroinflammation and indirect neurotoxicity. But despite the critical importance of CXCR4 and CCR5 signaling to HIV pathogenesis, there is only one therapeutic (the CCR5 inhibitor Maraviroc) that targets these receptors. Moreover, our understanding of co-receptor signaling in the specific context of neuroHIV is relatively poor. Research into co-receptor signaling has largely stalled in the past decade, possibly owing to the complexity of the signaling cascades and functions mediated by these receptors. Examining the many signaling pathways triggered by co-receptor activation has been challenging due to the lack of specific molecular tools targeting many of the proteins involved in these pathways and the wide array of model systems used across these experiments. Studies examining the impact of co-receptor signaling on HIV neuropathogenesis often show activation of multiple overlapping pathways by similar stimuli, leading to contradictory data on the effects of co-receptor activation. To address this, we will broadly review HIV infection and neuropathogenesis, examine different co-receptor mediated signaling pathways and functions, then discuss the HIV mediated signaling and the differences between activation induced by HIV and cognate ligands. We will assess the specific effects of co-receptor activation on neuropathogenesis, focusing on neuroinflammation. We will also explore how the use of substances of abuse, which are highly prevalent in people living with HIV, can exacerbate the neuropathogenic effects of co-receptor signaling. Finally, we will discuss the current state of therapeutics targeting co-receptors, highlighting challenges the field has faced and areas in which research into co-receptor signaling would yield the most therapeutic benefit in the context of HIV infection. This discussion will provide a comprehensive overview of what is known and what remains to be explored in regard to co-receptor signaling and HIV infection, and will emphasize the potential value of HIV co-receptors as a target for future therapeutic development.

中文翻译：

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神经HIV发病机制中的共受体信号传导

HIV 共受体 CCR5 和 CXCR4 是 HIV 进入靶细胞所必需的，它们与 HIV 包膜蛋白 gp120 相互作用，启动几个被认为对进入过程很重要的信号级联。共受体信号也可能通过促进持续性神经炎症和间接神经毒性来促进神经HIV的发展。但是，尽管 CXCR4 和 CCR5 信号传导对 HIV 发病机制至关重要，但只有一种治疗剂（CCR5 抑制剂 Maraviroc）针对这些受体。此外，我们对神经HIV特定背景下的共受体信号传导的理解相对较差。在过去十年中，对共受体信号传导的研究在很大程度上停滞不前，这可能是由于这些受体介导的信号级联和功能的复杂性。由于缺乏针对这些途径中涉及的许多蛋白质的特定分子工具以及这些实验中使用的广泛的模型系统，检查由共受体激活触发的许多信号通路一直具有挑战性。检查共同受体信号传导对 HIV 神经发病机制影响的研究通常表明，相似刺激会激活多个重叠通路，从而导致有关共同受体激活影响的相互矛盾的数据。为了解决这个问题，我们将广泛回顾 HIV 感染和神经发病机制，检查不同的共受体介导的信号通路和功能，然后讨论 HIV 介导的信号传导以及 HIV 和同源配体诱导的激活之间的差异。我们将评估共同受体激活对神经发病机制的具体影响，专注于神经炎症。我们还将探讨在 HIV 感染者中非常普遍的滥用物质的使用如何加剧共同受体信号传导的神经致病作用。最后，我们将讨论针对共同受体的治疗的现状，强调该领域面临的挑战以及共同受体信号传导研究将在 HIV 感染的背景下产生最大治疗益处的领域。本次讨论将全面概述共同受体信号传导和 HIV 感染方面的已知和尚待探索的内容，并将强调 HIV 共同受体作为未来治疗发展目标的潜在价值。可加剧共同受体信号传导的神经致病作用。最后，我们将讨论针对共同受体的治疗的现状，强调该领域面临的挑战以及共同受体信号传导研究将在 HIV 感染的背景下产生最大治疗益处的领域。本次讨论将全面概述共同受体信号传导和 HIV 感染方面的已知和尚待探索的内容，并将强调 HIV 共同受体作为未来治疗发展目标的潜在价值。可加剧共同受体信号传导的神经致病作用。最后，我们将讨论针对共同受体的治疗的现状，强调该领域面临的挑战以及共同受体信号传导研究将在 HIV 感染的背景下产生最大治疗益处的领域。本次讨论将全面概述共同受体信号传导和 HIV 感染方面的已知和尚待探索的内容，并将强调 HIV 共同受体作为未来治疗发展目标的潜在价值。突出该领域面临的挑战以及在艾滋病毒感染的情况下对共同受体信号传导的研究将产生最大治疗益处的领域。本次讨论将全面概述共同受体信号传导和 HIV 感染方面的已知和尚待探索的内容，并将强调 HIV 共同受体作为未来治疗发展目标的潜在价值。突出该领域面临的挑战以及在艾滋病毒感染的情况下对共同受体信号传导的研究将产生最大治疗益处的领域。本次讨论将全面概述共同受体信号传导和 HIV 感染方面的已知和尚待探索的内容，并将强调 HIV 共同受体作为未来治疗发展目标的潜在价值。