PNAS：胞外ATP诱导HIV-1从巨噬细胞中快速释放

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        HIV-1（1型HIV）病毒会感染CD4+ T淋巴细胞和巨噬细胞。被感染的巨噬细胞和T淋巴细胞在两个方面存在差异，其一是，很少或者完全不存在细胞的病变，其二是新复制产生的HIV病毒颗粒，开始在携带HIV病毒的巨噬细胞（ virus-containing compartments，VCC）中聚集。因此，巨噬细胞就像特诺伊木马一样，携带者大量的HIV病毒颗粒，遭遇细胞坏死因子的时候，巨噬细胞破裂并释放出HIV病毒。

        在新一期的《美国科学院院刊》中发表了一篇文章讨论细胞外ATP信号如何影响HIV病毒颗粒从巨噬细胞释放到环境中。论文中，作者讨论了一个可能的假说，就是细胞外的ATP（细胞能量货币，通过裂解高能磷酸键释放化学能）可能作为一种信号，形成一种微环境，能够影响病毒颗粒从携带HIV的巨噬细胞中的释放。实际上，细胞外ATP能够触发紧急感染HIV-1（CCR5相关HIV-1株）的人类单核细胞源性巨噬细胞中的病毒颗粒的释放。值得注意的是，细胞外ATP并不会造成巨噬细胞的裂解，凋亡或者原生性细胞死亡。病毒的释放也不是通过ATP的氧化作用。



         细胞内一种受体蛋白P2X7的抑制剂，能够抑制ATP刺激细胞释放病毒的效果，就是说细胞外ATP引起病毒释放是与P2X7相关的。可能的机制是，ATP通过和P2X7的接触，一起导致了HIV病毒颗粒从巨噬细胞中释放出来，而不会造成明显的细胞病变。这个研究意味着，在巨噬细胞中存留下来的HIV可以利用宿主细胞的机制释放而不会造成宿主巨噬细胞很大损伤。

         该研究从机理上揭示了HIV如何从巨噬细胞中释放。整个途径提供了潜在的抗HIV的药物靶点，即通过抑制P2X7受体蛋白就可以抑制HIV病毒的释放。这为HIV药物研发提供了新的思路。

（来源：生物谷Bioon.com）

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Extracellular ATP induces the rapid release of HIV-1 from virus containing compartments of human macrophages

Francesca Grazianoa,b, Marion Desdouitsc, Livia Garzettid, Paola Podinid, Massimo Alfanoa,1, Anna Rubartellie, Roberto Furland, Philippe Benarochc, and Guido Polia,b,f,2

HIV type 1 (HIV-1) infects CD4+ T lymphocytes and tissue macrophages. Infected macrophages differ from T cells in terms of decreased to absent cytopathicity and for active accumulation of new progeny HIV-1 virions in virus-containing compartments (VCC). For these reasons, infected macrophages are believed to act as “Trojan horses” carrying infectious particles to be released on cell necrosis or functional stimulation. Here we explored the hypothesis that extracellular ATP (eATP) could represent a microenvironmental signal potentially affecting virion release from VCC of infected macrophages. Indeed, eATP triggered the rapid release of infectious HIV-1 from primary human monocyte-derived macrophages (MDM) acutely infected with the CCR5-dependent HIV-1 strain. A similar phenomenon was observed in chronically infected promonocytic U1 cells differentiated to macrophage-like cells (D-U1) by costimulation with phorbol esters and urokinase-type plasminogen activator. Worthy of note, eATP did not cause necrotic, apoptotic, or pyroptotic cell death, and its effect on HIV-1 release was suppressed by Imipramine (an antidepressant agent known to inhibit microvesicle formation by interfering with membrane-associated acid sphingomyelinase). Virion release was not triggered by oxidized ATP, whereas the effect of eATP was inhibited by a specific inhibitor of the P2X7 receptor (P2X7R). Thus, eATP triggered the discharge of virions actively accumulating in VCC of infected macrophages via interaction with the P2X7R in the absence of significant cytopathicity. These findings suggest that the microvesicle pathway and P2X7R could represent exploitable targets for interfering with the VCC-associated reservoir of infectious HIV-1 virions in tissue macrophages.

http://www.pnas.org/content/112/25/E3265.full

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P2X7是一种ATP门控的K+通道。结合ATP后，通道打开，细胞内K+顺化学势梯度流出，这时会激活包膜上的电压门控Ca2+通道，引起钙离子改变，钙离子对于胞内的膜泡转运和融合是必须的，这可能会促进virus-containing compartments (VCC)的转移到膜上。作者应该检测下胞内钙离子浓度情况，来试验这种机制的可能性。

另外，我们在做炎性小体时会用LPS+ATP刺激巨噬细胞激活炎性小体产生IL-1 beta和IL-18。HIV感染巨噬细胞也可以激活炎性小体，额外的ATP刺激促进VCC的释放，是否有这些炎性因子的参与值得研究。