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 30, 425–435 (2023). https://doi.org/10.1038/s41594-023-00925-9
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.