HIV-1 nuclear import is selective and depends on both capsid elasticity and nuclear pore adaptability

作者：Zhen Hou, Y. Shen, Stanley Fronik, Juan Shen, Jiong Shi, Jialu Xu, Long Chen, Nathan Hardenbrook, Alan Engelman, Christopher Aiken, Peijun Zhang · 发表于：Nature Microbiology · 年份：2025 · DOI：10.1038/s41564-025-02054-z · 被引用次数：27 · 研究领域：HIV Research and Treatment、Nuclear Structure and Function、RNA Research and Splicing

Lentiviruses, such as HIV-1, infect non-dividing cells by traversing the nuclear pore complex (NPC); however, the detailed molecular processes remain unclear. Here we reconstituted functional HIV-1 nuclear import using permeabilized T cells and isolated HIV-1 cores, which significantly increases import events, and developed an integrated three-dimensional cryo-correlative workflow to specifically target and image 1,489 native HIV-1 cores at 4 distinct nuclear import stages using cryo-electron tomography. We found HIV-1 nuclear import depends on both capsid elasticity and nuclear pore adaptability. The NPC acts as a selective filter, preferentially importing smaller cores, while expanding and deforming to accommodate their passage. Brittle mutant cores fail to enter the NPC, while CPSF6-binding-deficient cores enter but stall within the NPC, leading to impaired nuclear import. This study uncovers the interplay between the HIV-1 core and the NPC and provides a framework to dissect HIV-1 nuclear import and downstream events, such as uncoating and integration.