Human immunodeficiency virus type 1 (HIV-1) has remained one of the most formidable challenges to human health since the first reported case in 1981, causing approximately 42.3 million deaths in total and over a million new infections every year.
Despite advances in treatment, there is still no cure to fully eradicate the virus once infected. A key reason why HIV-1 is so persistent is its ability to insert its genetic material into the DNA of host cells, especially CD4+ T cells and macrophages, creating a lifelong infection. To do this, the virus must deliver its genetic material, protected within a protein shell called the capsid, with other viral proteins named as the viral core, into the cell nucleus through a tightly controlled structure known as the nuclear pore complex (NPC). Exactly how HIV-1 navigates this highly controlled gateway has remained a mystery.
A team of researchers in Professor Peijun Zhang’s lab in the Division of Structural Biology (STRUBI) has achieved a breakthrough in understanding how HIV-1 traverses through the NPC into the nucleus of human cells. Using a combination of state-of-the-art cryo-electron microscopy techniques, the scientists captured nearly 1,500 viral cores in the act of nuclear import, a fleeting and elusive step in HIV-1’s life cycle.
The study, published in Nature Microbiology, establishes a robust cell-permeabilisation system that mimics the conditions of HIV-1 infection on the nuclear import process. This is then followed by the development of an advanced cryo-correlative workflow, combining cryo-CLEM, cryo-FIB milling, and cryo-electron tomography to snapshot HIV-1 as it interacts with the NPC.
The results reveal that successful nuclear entry depends not just on the shape and flexibility of viral core, but also on the NPC’s adaptability and host cell factors like CPSF6. The nuclear pores themselves act as selective gates, favouring smaller and tubular cores and the passage of HIV-1 leads to the expansion and deformation of NPCs. Brittle viral cores fail to enter the pore, while mutants that can’t bind CPSF6 get stuck inside the NPC, unable to proceed into the nucleus. These findings highlight a finely tuned interplay between HIV-1 and the human NPC.
Prof Zhang, Professor of Structural Biology and Wellcome Trust Investigator at STRUBI, said: ‘These insights could have profound implications for antiviral strategies and open new avenues for studying what happens after the virus gets inside the nucleus, especially how it sheds its outer shell and integrates into the host genome. The system and workflow developed in this study also provide a powerful platform for in situ analysis of diverse nuclear processes with broad biological relevance. This work marks a major leap forward in visualising HIV at its most critical stage and understanding how to potentially stop it.’
Read the full paper on the Nature website: https://www.nature.com/articles/s41564-025-02054-z