Two HIV-1 variants resistant to small molecule CCR5 inhibitors differ in how they use CCR5 for entry.
Two HIV-1 variants resistant to small molecule CCR5 inhibitors differ in how they use CCR5 for entry.
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DOI：
10.1371/journal.ppat.1000548
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发表时间：
2009-08
期刊：
影响因子：
6.7
通讯作者：
Moore JP
中科院分区：
文献类型：
--
作者：
Berro R;Sanders RW;Lu M;Klasse PJ;Moore JP
对小分子CCR 5抑制剂具有抗性的HIV-1变异体识别CCR 5复合物，同时也与游离CCR 5相互作用。最常见的耐药遗传途径涉及gp 120 V3区域的序列变化，这是当原代分离株CC 1/85与AD 101抑制剂体外培养时遵循的途径，产生了CC101.19耐药变体。然而，D1/86.16逃逸突变体不包含V3变化，但在gp 41融合肽中有三个取代。通过使用CCR 5点突变体和gp 120靶向剂，我们研究了来自亲本和两种耐药分离株的感染性克隆病毒如何与CCR 5相互作用。我们得出结论，CC101.19 cl.7中的V3序列变化产生了对与CCR 5 N-末端相互作用的依赖性增加的病毒。与V3区相关的CCR 5结合位点的元件和gp 120桥接片中的CD 4诱导的（CD 4 i）表位簇更多地暴露在CC101.19 cl.7的天然Env复合物上，其对通过这些表位的中和敏感。然而，D1/86.16 cl.23对CCR 5 N-末端的依赖性没有增加，并且其CCR 5结合位点没有变得更加暴露。这种病毒如何与CCR 5复合物相互作用仍有待了解。人类免疫缺陷病毒1型（HIV-1）是艾滋病的病原体。HIV-1进入靶细胞是由病毒包膜糖蛋白与细胞表面受体（CD 4）和辅助受体（CCR 5）的相互作用触发的，并在病毒和细胞膜的融合中达到高潮。与CCR 5结合的小分子抑制剂是一类用于治疗HIV-1感染者的新药。然而，HIV-1可以通过获得改变其包膜糖蛋白（gp 120-gp 41）与CCR 5相互作用的突变来进化出对这些化合物产生抗性的方法。在这项研究中，我们研究了两种耐药病毒如何通过两种不同的机制获得使用CCR 5结合形式的能力。在第一种病毒中，gp 120的V3区中的四个氨基酸取代产生了对与CCR 5 N-末端相互作用的依赖性增加。这些变化改变了gp 120的构型，增加了V3区和与CCR 5结合位点相关的CD 4 i表位簇中抗体表位的暴露。相比之下，第二种病毒通过gp 41亚基中的三个序列变化变得具有抗性，并没有变得更加依赖于CCR 5 N-末端，并且仍然对针对CCR 5结合位点的元件的抗体的中和具有抗性。
HIV-1 variants resistant to small molecule CCR5 inhibitors recognize the inhibitor-CCR5 complex, while also interacting with free CCR5. The most common genetic route to resistance involves sequence changes in the gp120 V3 region, a pathway followed when the primary isolate CC1/85 was cultured with the AD101 inhibitor in vitro, creating the CC101.19 resistant variant. However, the D1/86.16 escape mutant contains no V3 changes but has three substitutions in the gp41 fusion peptide. By using CCR5 point-mutants and gp120-targeting agents, we have investigated how infectious clonal viruses derived from the parental and both resistant isolates interact with CCR5. We conclude that the V3 sequence changes in CC101.19 cl.7 create a virus with an increased dependency on interactions with the CCR5 N-terminus. Elements of the CCR5 binding site associated with the V3 region and the CD4-induced (CD4i) epitope cluster in the gp120 bridging sheet are more exposed on the native Env complex of CC101.19 cl.7, which is sensitive to neutralization via these epitopes. However, D1/86.16 cl.23 does not have an increased dependency on the CCR5 N-terminus, and its CCR5 binding site has not become more exposed. How this virus interacts with the inhibitor-CCR5 complex remains to be understood. Human immunodeficiency virus type 1 (HIV-1) is the causative agent of AIDS. HIV-1 entry into target cells is triggered by the interaction of the viral envelope glycoproteins with a cell-surface receptor (CD4) and a co-receptor (CCR5), and culminates in fusion of the viral and cell membranes. Small molecule inhibitors that bind to CCR5 are a new class of drug for treating HIV-1-infected people. However, HIV-1 can evolve ways to become resistant to these compounds, by acquiring mutations that alter how its envelope glycoproteins (gp120-gp41) interact with CCR5. In this study, we investigated how two resistant viruses gained the ability to use the inhibitor-bound form of CCR5 through two different mechanisms. In the first virus, four amino acid substitutions in the V3 region of gp120 created an increased dependency on interactions with the CCR5 N-terminus. These changes altered the configuration of gp120, increasing the exposure of antibody epitopes in the V3 region and the CD4i epitope cluster associated with the CCR5 binding site. In contrast, the second virus, which became resistant via three sequence changes in the gp41 subunit, did not become more dependent on the CCR5 N-terminus and remained resistant to neutralization by antibodies against elements of the CCR5 binding site.
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影响因子：
5.4
作者：
Genoud, S;Kajumo, F;Dragic, T
通讯作者：
Dragic, T
DOI：
10.1073/pnas.0811713106
发表时间：
2009-03-31
影响因子：
11.1
作者：
Anastassopoulou, Cleo G.;Ketas, Thomas J.;Moore, John P.
通讯作者：
Moore, John P.
影响因子：
3.6
作者：
Kondru, Rama;Zhang, Jun;Dioszegi, Marianna
通讯作者：
Dioszegi, Marianna
影响因子：
56.9
作者：
Huang, Chih-chin;Lam, Son N.;Kwong, Peter D.
通讯作者：
Kwong, Peter D.
影响因子：
5.4
作者：
Cormier, EG;Dragic, T
通讯作者：
Dragic, T