Modeling HIV-1 nuclear entry with nucleoporin-gated DNA-origami channels.

Qi Shen, Qingzhou Feng, Chunxiang Wu, Qiancheng Xiong, Taoran Tian, Shuai Yuan, Jiong Shi, Gregory J Bedwell, Ran Yang, Christopher Aiken, Alan N Engelman, C Patrick Lusk, Chenxiang Lin, Yong Xiong

Nature structural & molecular biology 2023 Apr

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Delivering the virus genome into the host nucleus through the nuclear pore complex (NPC) is pivotal in human immunodeficiency virus 1 (HIV-1) infection. The mechanism of this process remains mysterious owing to the NPC complexity and the labyrinth of molecular interactions involved. Here we built a suite of NPC mimics-DNA-origami-corralled nucleoporins with programmable arrangements-to model HIV-1 nuclear entry. Using this system, we determined that multiple cytoplasm-facing Nup358 molecules provide avid binding for capsid docking to the NPC. The nucleoplasm-facing Nup153 preferentially attaches to high-curvature regions of the capsid, positioning it for tip-leading NPC insertion. Differential capsid binding strengths of Nup358 and Nup153 constitute an affinity gradient that drives capsid penetration. Nup62 in the NPC central channel forms a barrier that viruses must overcome during nuclear import. Our study thus provides a wealth of mechanistic insight and a transformative toolset for elucidating how viruses like HIV-1 enter the nucleus. © 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

Citation

Qi Shen, Qingzhou Feng, Chunxiang Wu, Qiancheng Xiong, Taoran Tian, Shuai Yuan, Jiong Shi, Gregory J Bedwell, Ran Yang, Christopher Aiken, Alan N Engelman, C Patrick Lusk, Chenxiang Lin, Yong Xiong. Modeling HIV-1 nuclear entry with nucleoporin-gated DNA-origami channels. Nature structural & molecular biology. 2023 Apr;30(4):425-435