Scientists capture HIV-1 viral cores entering the nucleus in unprecedented detail

In a recent landmark study, scientists have unveiled how HIV-1 penetrates the cell’s nuclear barrier—a discovery that could reshape antiviral strategies. The research, led by Professor Peijun Zhang, eBIC director at Diamond, used cutting-edge cryo-electron microscopy to capture HIV-1 viral cores in the process of nuclear import—an elusive but critical step in the virus’s life cycle.

These insights, published in Nature Microbiology, were made possible by the cryo-EM facilities available at eBIC, the UK National Electron Bio-Imaging Centre. The researchers, from Professor Zhang’s lab at the University of Oxford, used cell-permeabilization, a technique to make the cell membrane porous without destroying the cell. They were able to mimic how HIV infects human cells and captured nearly 1,500 viral cores entering a cell’s nucleus.

The study revealed that HIV-1’s success in entering the nucleus relies on the shape and flexibility of its viral cores, the adaptability of the nuclear pore complex (NPC), and host factors like CPSF6.

CPSF6 is a host cell protein that plays a crucial role in the early stages of HIV-1 infection, particularly in how the virus enters the nucleus and integrates into the host genome.

The nuclear pore, the gateway to the cell’s nucleus, was thought to have a rigid, fixed structure that only allowed certain molecules through. The study shows that the nuclear pore is far more able to adapt—it can expand and change shape to help parts of the HIV virus (the viral cores) to pass through.

However, not all viral cores pass into the nucleus; if the core is too fragile or it can’t connect with the protein CPSF6, it gets stuck at the pore or left outside. This means the nuclear pore isn’t just a passive doorway, it plays an active role in deciding which viruses can enter. This is a major new understanding in HIV infection and how the virus interacts with our cells.

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 over 42 million deaths in total and over 1 million new infections every year. The findings not only deepen our understanding of HIV-1 but also demonstrate the power of in situ structural biology to illuminate complex cellular processes.

This work marks a major leap forward in visualizing HIV at its most critical stage and understanding how to potentially stop it.