A small molecule compound IMB-LA inhibits HIV-1 infection by preventing viral Vpu from antagonizing the host restriction factor BST-2.
A small molecule compound IMB-LA inhibits HIV-1 infection by preventing viral Vpu from antagonizing the host restriction factor BST-2.
复制标题
小分子化合物 IMB-LA 通过阻止病毒 Vpu 拮抗宿主限制因子 BST-2 来抑制 HIV-1 感染。
DOI：
10.1038/srep18499
复制
发表时间：
2015-12-16
影响因子：
4.6
通讯作者：
Cen S
中科院分区：
文献类型：
--
作者：
Mi Z;Ding J;Zhang Q;Zhao J;Ma L;Yu H;Liu Z;Shan G;Li X;Zhou J;Wei T;Zhang L;Guo F;Liang C;Cen S
人BST-2通过将新生病毒粒子束缚在细胞表面来抑制HIV-1复制。HIV-1编码Vpu，通过下调细胞表面的这种限制因子来抵消BST-2。这一重要功能使Vpu成为潜在的治疗靶点。然而，没有药物被报道能阻断Vpu拮抗BST-2。在这项研究中，我们报告了一种小分子化合物IMB-LA，它废除了Vpu的功能，从而通过使病毒对BST-2限制敏感来强烈抑制HIV-1复制。进一步的研究表明，IMB-LA特异性抑制Vpu介导的BST-2降解，并恢复BST-2在细胞表面的表达。尽管IMB-LA不能阻止Vpu与BST-2或含β-TrCP 2的泛素E3连接酶相互作用，但在Vpu表达细胞中BST-2分选到溶酶体中被IMB-LA阻断。最重要的是，IMB-LA仅在表达BST-2的细胞中抑制HIV-1的释放和感染。总之，本文的结果表明，IMB-LA可以特异性地抑制由Vpu诱导的BST-2的降解，并以BST-2依赖的方式损害HIV-1的复制，这表明利用小分子化合物使Vpu的拮抗剂功能失效，从而使HIV-1暴露于BST-2的限制的可行性。
Human BST-2 inhibits HIV-1 replication by tethering nascent virions to the cell surface. HIV-1 codes Vpu that counteracts BST-2 by down-regulating this restriction factor from the cell surface. This important function makes Vpu a potential therapeutic target. Yet, no agents have been reported to block Vpu from antagonizing BST-2. In this study, we report a small molecule compound IMB-LA that abrogates the function of Vpu and thereby strongly suppresses HIV-1 replication by sensitizing the virus to BST-2 restriction. Further studies revealed that IMB-LA specifically inhibits Vpu-mediated degradation of BST-2 and restores the expression of BST-2 at the cell surface. Although IMB-LA does not prevent Vpu from interacting with BST-2 or β-TrCP2-containing ubiquitin E3 ligase, sorting of BST-2 into lysosomes in Vpu-expressing cells is blocked by IMB-LA. Most importantly, HIV-1 release and infection is inhibited by IMB-LA only in BST-2-expressing cells. In summary, results herein demonstrated that IMB-LA could specifically inhibit the degradation of BST-2 induced by Vpu and impair HIV-1 replication in a BST-2 dependent manner, suggesting the feasibility of utilizing small molecule compounds to disable the antagonist function of Vpu and thereby expose HIV-1 to the restriction by BST-2.
影响因子：
3.7
作者：
Ruiz A;Lau D;Mitchell RS;Hill MS;Schmitt K;Guatelli JC;Stephens EB
通讯作者：
Stephens EB