P2X1 Selective Antagonists Block HIV-1 Infection through Inhibition of Envelope Conformation-Dependent Fusion
P2X1 Selective Antagonists Block HIV-1 Infection through Inhibition of Envelope Conformation-Dependent Fusion
复制标题
P2X1选择性拮抗剂通过抑制包膜构象依赖性融合来阻断HIV-1感染
DOI：
10.1128/jvi.01622-19
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发表时间：
2020-03-01
影响因子：
5.4
通讯作者：
Swartz, Talia H.
中科院分区：
文献类型：
--
作者：
Soare, Alexandra Y.;Malik, Hagerah S.;Swartz, Talia H.
嘌呤能受体是炎症过程的公认调节剂，主要通过检测由死亡或感染细胞释放的细胞外核苷酸。新兴文献已经证明，抑制这些炎症受体可以阻断HIV-1产生性感染和HIV-1相关炎症。受体类型的特异性和相互作用机制尚未确定。在这里，我们的特点P2 X1受体拮抗剂，NF 279和NF 449，在细胞系，原代细胞，和各种HIV-1包膜（Env）的分支的抑制活性。NF 279和NF 449在病毒膜融合水平阻断生产性感染，对不同的HIV-1 Env分离株具有一系列抑制活性。携带HIV-1 Env糖蛋白41（gp 41）C-末端尾部截短缺失的突变病毒显示对P2 X1拮抗剂的敏感性降低，表明这些分子的抑制敏感性可能受Env构象的调节。相反，P2 X7拮抗剂A438079对生产性感染和融合的影响有限。NF 279和NF 449干扰gp 120可变区1和2（V1 V2）靶向的广泛中和抗体PG 9阻断生产性感染的能力，表明这些药物可能拮抗HIV-1 Env在gp 120 V1 V2阻断病毒膜融合。我们的观察表明，P2 X1拮抗作用可以通过与Env相互作用在病毒膜融合水平上抑制HIV-1复制。未来的研究将探讨这些化合物在抑制HIV-1融合和发展的小分子阻断HIV-1进入通过这种mechanism.IMPORTANCE虽然有效的治疗可以降低严重的发病率和死亡率与HIV-1感染，感染HIV-1的患者患有慢性炎症相关的非传染性合并症的显着较高的利率。新兴文献表明P2 X1受体在介导这种慢性炎症中起关键作用，但其机制仍不清楚。在这里，我们证明，HIV-1感染减少P2 X1受体拮抗作用。这种抑制是通过干扰HIV-1 Env介导的，可以影响多种病毒进化枝。这些观察结果突出了P2 X1拮抗剂作为潜在的新型治疗剂的重要性，其可以用于阻断各种不同的病毒进化枝，并具有抗炎特性的额外益处。
Purinergic receptors are well-established modulators of inflammatory processes, primarily through detection of extracellular nucleotides that are released by dying or infected cells. Emerging literature has demonstrated that inhibition of these inflammatory receptors can block HIV-1 productive infection and HIV-1-associated inflammation. The specificity of receptor type and mechanism of interaction has not yet been determined. Here, we characterize the inhibitory activity of P2X1 receptor antagonists, NF279 and NF449, in cell lines, primary cells, and a variety of HIV-1 envelope (Env) clades. NF279 and NF449 blocked productive infection at the level of viral membrane fusion, with a range of inhibitory activities against different HIV-1 Env isolates. A mutant virus carrying a truncation deletion of the C-terminal tail of HIV-1 Env glycoprotein 41 (gp41) showed reduced sensitivity to P2X1 antagonists, indicating that the sensitivity of inhibition by these molecules may be modulated by Env conformation. In contrast, a P2X7 antagonist, A438079, had a limited effect on productive infection and fusion. NF279 and NF449 interfered with the ability of the gp120 variable regions 1 and 2 (V1V2)-targeted broadly neutralizing antibody PG9 to block productive infection, suggesting that these drugs may antagonize HIV-1 Env at gp120 V1V2 to block viral membrane fusion. Our observations indicate that P2X1 antagonism can inhibit HIV-1 replication at the level of viral membrane fusion through interaction with Env. Future studies will probe the nature of these compounds in inhibiting HIV-1 fusion and the development of small molecules to block HIV-1 entry via this mechanism.IMPORTANCE While effective treatment can lower the severe morbidity and mortality associated with HIV-1 infection, patients infected with HIV-1 suffer from significantly higher rates of noncommunicable comorbidities associated with chronic inflammation. Emerging literature suggests a key role for P2X1 receptors in mediating this chronic inflammation, but the mechanism is still unknown. Here, we demonstrate that HIV-1 infection is reduced by P2X1 receptor antagonism. This inhibition is mediated by interference with HIV-1 Env and can impact a variety of viral clades. These observations highlight the importance of P2X1 antagonists as potential novel therapeutics that could serve to block a variety of different viral clades with additional benefits for their anti-inflammatory properties.