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.
Read the full story on the Nuffield Department of Medicine website.