Division of Infectious Diseases, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
Department of Biochemistry & Molecular Genetics, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
Nat Commun. 2022 Oct 6;13(1):5879. doi: 10.1038/s41467-022-33662-6.
Cellular proteins CPSF6, NUP153 and SEC24C play crucial roles in HIV-1 infection. While weak interactions of short phenylalanine-glycine (FG) containing peptides with isolated capsid hexamers have been characterized, how these cellular factors functionally engage with biologically relevant mature HIV-1 capsid lattices is unknown. Here we show that prion-like low complexity regions (LCRs) enable avid CPSF6, NUP153 and SEC24C binding to capsid lattices. Structural studies revealed that multivalent CPSF6 assembly is mediated by LCR-LCR interactions, which are templated by binding of CPSF6 FG peptides to a subset of hydrophobic capsid pockets positioned along adjoining hexamers. In infected cells, avid CPSF6 LCR-mediated binding to HIV-1 cores is essential for functional virus-host interactions. The investigational drug lenacapavir accesses unoccupied hydrophobic pockets in the complex to potently impair HIV-1 inside the nucleus without displacing the tightly bound cellular cofactor from virus cores. These results establish previously undescribed mechanisms of virus-host interactions and antiviral action.
细胞蛋白 CPSF6、NUP153 和 SEC24C 在 HIV-1 感染中发挥关键作用。虽然已经研究了含有短苯丙氨酸-甘氨酸 (FG) 的肽与分离的衣壳六聚体的弱相互作用，但这些细胞因子如何与生物相关的成熟 HIV-1 衣壳晶格功能性结合尚不清楚。在这里，我们表明朊病毒样低复杂度区域 (LCR) 使 CPSF6、NUP153 和 SEC24C 能够与衣壳晶格强烈结合。结构研究表明，多价 CPSF6 组装是由 LCR-LCR 相互作用介导的，该相互作用由 CPSF6 FG 肽与沿相邻六聚体定位的一组疏水性衣壳口袋的结合模板化。在受感染的细胞中，HIV-1 核心中 CPSF6 LCR 介导的结合对于功能性病毒-宿主相互作用至关重要。研究药物 lenacapavir 可进入复杂结构中未被占据的疏水性口袋，从而有效地抑制细胞核内的 HIV-1，而不会从病毒核心中置换紧密结合的细胞辅助因子。这些结果确立了以前未知的病毒-宿主相互作用和抗病毒作用机制。
