Strengths and weaknesses of an HIV drug Retroviruses replicate by inserting a copy of their RNA, which has been reverse transcribed into DNA, into the host genome. This process involves the intasome, a nucleoprotein complex comprising copies of the viral integrase bound at the ends of the viral DNA. HIV integrase strand-transfer inhibitors (INSTIs) stop HIV from replicating by blocking the viral integrase and are widely used in HIV treatment. Cook et al. describe structures of second-generation inhibitors bound to the simian immunodeficiency virus (SIV) intasome and to an intasome with integrase mutations known to cause drug resistance. Passos et al. describe the structures of the HIV intasome bound to a second-generation inhibitor and to developmental compounds that are promising drug leads. These structures show how mutations can cause subtle changes in the active site that affect drug binding, show the basis for the higher activity of later-generation inhibitors, and may guide development of better drugs. Science, this issue p. 806, p. 810 Single-particle cryo–electron microscopy shows how inhibitors that bind the intasome may allow the development of better drugs against HIV. The HIV intasome is a large nucleoprotein assembly that mediates the integration of a DNA copy of the viral genome into host chromatin. Intasomes are targeted by the latest generation of antiretroviral drugs, integrase strand-transfer inhibitors (INSTIs). Challenges associated with lentiviral intasome biochemistry have hindered high-resolution structural studies of how INSTIs bind to their native drug target. Here, we present high-resolution cryo–electron microscopy structures of HIV intasomes bound to the latest generation of INSTIs. These structures highlight how small changes in the integrase active site can have notable implications for drug binding and design and provide mechanistic insights into why a leading INSTI retains efficacy against a broad spectrum of drug-resistant variants. The data have implications for expanding effective treatments available for HIV-infected individuals.

中文翻译：

---

链转移抑制剂与 HIV 嵌体结合的结构基础


HIV 药物的优点和缺点 逆转录病毒通过将已逆转录为 DNA 的 RNA 副本插入宿主基因组来进行复制。这个过程涉及整合体，一种核蛋白复合物，包含结合在病毒 DNA 末端的病毒整合酶的副本。 HIV 整合酶链转移抑制剂 (INSTI) 通过阻断病毒整合酶来阻止 HIV 复制，并广泛用于 HIV 治疗。库克等人。描述了与猿猴免疫缺陷病毒（SIV）嵌体和具有已知导致耐药性的整合酶突变的嵌体结合的第二代抑制剂的结构。帕索斯等人。描述了与第二代抑制剂和有希望的药物先导化合物结合的 HIV 嵌体的结构。这些结构表明突变如何引起影响药物结合的活性位点的微妙变化，为下一代抑制剂的更高活性奠定了基础，并可能指导更好药物的开发。科学，本期第 14 页。 806，p。 810 单颗粒冷冻电子显微镜显示结合整合体的抑制剂如何能够开发出更好的抗 HIV 药物。 HIV 整合体是一种大型核蛋白组装体，介导病毒基因组 DNA 拷贝整合到宿主染色质中。 Intasome 是最新一代抗逆转录病毒药物整合酶链转移抑制剂 (INSTI) 的靶点。与慢病毒嵌体生物化学相关的挑战阻碍了对 INSTI 如何与其天然药物靶点结合的高分辨率结构研究。在这里，我们展示了与最新一代 INSTI 结合的 HIV 嵌体的高分辨率冷冻电子显微镜结构。 这些结构强调了整合酶活性位点的微小变化如何对药物结合和设计产生显着影响，并提供了为什么领先的 INSTI 对广谱耐药变异保持疗效的机制见解。这些数据对于扩大艾滋病毒感染者的有效治疗方法具有重要意义。