Herpes Virus Fluidizes Cell Nuclei to Multiply Faster

NEW YORK, March 5, 2026 /PRNewswire/ -- Herpes simplex virus partially liquifies the tightly packed, gel-like interior of human cell nuclei to copy itself faster, a new study shows.

The research centers on how the nucleus of each human cell houses the genetic machinery used to copy DNA-encoded instructions when it divides and multiplies as part of growth. Viruses invade human cells and use their machinery to copy themselves, but the invasion can be hindered by the dense structure of the nucleus.

Led by researchers at NYU Langone Health, the new study found that herpes simplex virus uses a protein called infected cell protein 4 (ICP4) to make the human nucleus more fluid-like, which in turn makes it easier for the virus to replicate itself. Publishing online March 5 in Molecular Cell, the work revealed that blocking the ability of ICP4 to fluidize the nuclear compartment caused a four-fold drop in the production rate of new viral copies.

"The physical state of the nucleus is a fundamental barrier that a virus must overcome to multiply," says senior study author Liam Holt, PhD, a professor in the Department of Biochemistry and Molecular Pharmacology at NYU Langone Health and faculty in the Institute for Systems Genetics. "Viruses are masters at manipulating cells, and by studying their tricks, we uncover fundamental rules of biology."

The research team chose to study herpes simplex virus 1 because it is one of the most prevalent infectious diseases, with a 2025 study estimating that globally 64 percent of adults have become infected for life, although many without symptoms.

Room to Build

To multiply, say the authors, viruses need room to build relatively large structures called condensates – dense droplets that concentrate molecules. For HSV-1, condensates serve as temporary factories built inside the host nucleus to mass-produce viruses. If there is enough space to move, small droplets merge into larger ones, which the researchers think gathers the viral reproduction machinery in one place for greater efficiency.

The study authors theorize that herpes simplex makes space by taking advantage of a vital process that comes with structural changes in human nuclei. There, chains of DNA are known to be wrapped around protein spools called histones, all within a superstructure called chromatin. In a normal nucleus, the formation of viral condensate factories is hampered by the chromatin network, like trying to inflate a balloon inside a tight fishing net.

ICP4, the study authors say, is able to prepare human nuclei for viral replication because it attaches to the proteins that get human cells ready for transcription, the process by which a stretch of the gene code gets read by the cell's machinery to pass on its message. For any piece of code to be read, however, its surrounding chromatin must get the signal to unwind, which makes the DNA accessible to the transcription machinery.

Previous research had found that ICP4 attaches to chromatin remodeling protein groups that execute this unwinding, and changes the structure and motion of chromatin. The current study found that ICP4 alone caused chromatin motion to increase. Importantly, however, the authors did not see changes in the rate of the transcription that such motion typically precedes.

Thus, combined with earlier work, the study suggests that viral ICP4 attaches to the protein complexes that unwind DNA around histones, not to enable access to genes, but just to cause the unwinding. This motion changes chromatin's physical properties, loosening the nuclear interior to make possible viral condensate size increases, the researchers say. ICP4 can, they say, by itself and separately from other known processes, efficiently change the properties of the infected nucleus to help viral replication, and very early in an infection.

To measure the physical properties of nuclei, the research team engineered the cells to produce glowing protein nanoparticles called nucGEMs. The researchers recorded videos through microscopes to track the degree to which these particles moved as a measure of how thick the nuclear environment was. When the team then infected the cells with herpes simplex virus 1, the glowing particles bounced around to a much greater degree.

"We are working now to confirm the mechanism by which ICP4 fluidizes the nucleus, which could give us new, specific targets to physically counter viral replication," says first study author Nora Herzog, PhD, a recent graduate from the biomedical sciences program at NYU Langone, and now a postdoctoral fellow at Universitat de València Parc Cientific in Valencia, Spain. "We will also be looking to see if this mechanism is used by other viruses that replicate in the nucleus, from the double-stranded DNA viruses responsible for shingles to RNA viruses like influenza virus to retroviruses like HIV."

Along with Dr. Holt and Dr. Herzog, authors of the study from NYU Langone were Tong Shu, Gururaj Kidiyoor, Sarah Keegan, Ian Mohr, and Angus Wilson of the Institute for Systems Genetics, Department of Microbiology, and Department of Biochemistry and Molecular Pharmacology. Other authors were Farah Korchi of Université Paris Cité, David Chenoweth of the University of Pennsylvania, and Huaiying Zhang of Carnegie Mellon University.

Funding for the study was provided by National Institutes of Health (NIH) grants GM132447, AI176335, AI170583, GM056927, and AI073898; National Science Foundation (NSF) grant MCB-2145083, and the Hypothesis Fund.

About NYU Langone Health

NYU Langone Health is a fully integrated health system that consistently achieves the best patient outcomes through a rigorous focus on quality that has resulted in some of the lowest mortality rates in the nation. Vizient Inc. has ranked NYU Langone No. 1 out of 118 comprehensive academic medical centers across the nation for four years in a row, and U.S. News & World Report recently ranked four of its clinical specialties No. 1 in the nation. NYU Langone offers a comprehensive range of medical services with one high standard of care across seven inpatient locations, its Perlmutter Cancer Center, and more than 320 outpatient locations in the New York area and Florida. The system also includes two tuition-free medical schools, in Manhattan and on Long Island, and a vast research enterprise.

Contact:
Gregory Williams
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SOURCE NYU Langone