eBIC visualises how HIV highjacks human cells

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 University of Oxford, used a cell-permeabilisation, 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.

CEM cells showing green-labelled WT cores and magenta-stained nuclei, with arrows highlighting core signals inside the nucleus. Scale bar: 5 µm.

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 orf 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 visualising HIV at its most critical stage and understanding how to potentially stop it.