Researchers at Queen Mary University of London have uncovered a previously unknown mechanism by which HIV-1 infects resting immune cells. The findings challenge decades-old assumptions in HIV biology and open new avenues for understanding how the virus persists in the body despite treatment.
To successfully infect T cells, the immune cells that HIV primarily targets, HIV’s genetic material must be delivered to the cell’s nucleus. A highly protected compartment, the nucleus is surrounded by structures called nuclear pore complexes (NPCs), which act as selective gateways that control what goes in and out. The HIV capsid, the protective shell that surrounds HIV’s genetic material, is unusually large, and scientists have long puzzled how HIV gets through this barrier.
The new study, published today in Nature, reveals that when HIV spreads directly between T cells, it triggers a molecular signaling chain that temporarily unlocks the NPC, allowing the HIV virus and capsid to enter and integrate into the host’s DNA. The researchers found that this process does not require activation of T cells, overturning a long-held assumption in the field.
This finding has important implications for understanding one of the biggest obstacles to the treatment of HIV: the latent reservoir, the pool of resting T cells harboring dormant HIV. This reservoir acts as a permanent hiding place for the virus and is the main barrier to eliminating it from the body, as antiretroviral therapy cannot reach or remove the virus.
Scientists have long been puzzled by this contradiction. While these resting infected cells are easily detected in HIV-infected individuals, resting T cells have consistently resisted infection in laboratory experiments. This leads to the assumption that cells must first be activated before HIV can take hold and that these cells represent cells that were infected when previously activated but have returned to a dormant state.
This study provides a new explanation. This study shows that cell-to-cell transmission of HIV may render non-tolerant resting T cells susceptible to infection and suggests that a latent reservoir may be established and maintained through a previously unrecognized mechanism. The discovery could also have implications for treatment, providing new routes to destroy the virus and remove potential reservoirs.
Beyond HIV, this study reveals a previously uncharacterized mechanism of nuclear trafficking regulation in T cells, with potential implications for immunology and the development of new immunotherapies. A better understanding of how immune cell signaling shapes fundamental cell biological processes could inform approaches to control T cell behavior for therapeutic purposes.
Professor Claire Jolly, Professor of Virus and Cell Biology at Queen Mary University of London, said:
“What excites me most is how cleverly HIV-1 exploits the cell’s own machinery, and how we can use the virus as a molecular tool to discover how cells function, such as revealing exciting new biology about the control of nuclear transport, a fundamental cellular process. The nuclear pore complex is one of the most sophisticated structures in cells, and HIV-1 has evolved to manipulate it through highly specific pathways: CD4 signaling, CDK1 activation, and nucleoporin phosphorylation, which is triggered by the physical act of one cell coming into contact with another. This allows HIV-1 to externally modify the nuclear transport gateway and trigger a permissive switch that opens the door to infection. It is expected that other viruses may manipulate the nuclear transport machinery in similarly sophisticated ways to allow infection, and it will be interesting to see how this plays out.
“While our work is basic discovery science, we hope to advance our understanding of how resting T cell reservoirs are established and, based on our findings, uncover new avenues for therapeutically targeting HIV carriers. Ultimately, that is the ultimate goal: improving human health.”
It was really exciting to see how imaging allows us to observe CDK1-dependent remodeling of nuclear pore structures during HIV-1 infection in primary T cells. These imaging approaches, which combine live cell dynamics, quantitative subcellular localization, and nanoscale dSTORM reconstructions of NPC structures, provided mechanistic evidence that biochemical assays cannot achieve alone. We reveal not only that NPCs are modified, but also how that modification alleviates important obstacles to the HIV1 life cycle. ”
Dr Matt Whelan, Academic Lead for Blizzard Advanced Light Microscopy at Queen Mary and Wellcome Early Career Fellowship
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Queen Mary University of London
Reference magazines:
Messner, D. others. (2026). HIV-1 signaling remodels nuclear pores to permit infection. nature. DOI: 10.1038/s41586-026-10453-3. https://www.nature.com/articles/s41586-026-10453-3
