Prion-like low complexity regions enable avid virus-host interactions during HIV-1 infection

Cellular proteins CPSF6, NUP153 and SEC24C play crucial roles in HIV-1 infection. While weak interactions of short FG peptides to isolated capsid hexamers have been characterized, how these proteins engage biologically relevant extended HIV-1 capsid lattices is unknown. We have identified that prion-like low complexity regions (LCR) enable avid binding of CPSF6, NUP153 and SEC24C to curved hexameric capsid lattices. Structural studies reveal that LCR-LCR interactions mediate multivalent CPSF6 assembly, which are templated by binding of CPSF6 FG peptides to a subset of hydrophobic capsid pockets positioned along adjoining hexamers. CPSF6 LCR mediated avid binding to HIV-1 cores is essential for functional virus-host interactions in infected cells. Investigational drug lenacapavir can access unoccupied hydrophobic pockets in the CPSF6-HIV-1 complex and potently impair HIV-1 inside the nucleus without displacing the tightly bound cellular cofactor from virus cores. These results elucidate previously undescribed mechanisms of virus-host interactions and potent inhibition of HIV-1.

细胞蛋白CPSF6、NUP153与SEC24C在HIV-1感染进程中发挥关键作用。尽管学界已对短FG肽段与分离衣壳六聚体间的弱相互作用完成表征，但上述蛋白如何结合具有生物学相关性的延伸型HIV-1衣壳晶格，目前尚不明确。本研究鉴定发现，朊病毒样低复杂度区域（prion-like low complexity region，LCR）可介导CPSF6、NUP153及SEC24C与弯曲六聚体衣壳晶格产生高亲和结合。结构研究显示，LCR-LCR相互作用可介导多价CPSF6组装，该组装过程以CPSF6的FG肽段结合相邻六聚体上的部分疏水衣壳口袋为模板。CPSF6的LCR介导的对HIV-1衣壳核心的高亲和结合，对于感染细胞内功能性病毒-宿主相互作用不可或缺。在研药物来那卡帕韦（lenacapavir）可结合CPSF6-HIV-1复合物中未被占据的疏水口袋，能够在细胞核内强效抑制HIV-1，且不会将紧密结合的细胞辅因子从病毒衣壳核心中置换出去。本研究结果阐明了此前尚未被报道的病毒-宿主相互作用机制以及HIV-1的强效抑制策略。