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 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.