The herpes simplex virus partially liquefies the tightly packed gel-like interior of human cell nuclei to copy itself faster, a new study shows.
The research focuses on how the nucleus of each human cell houses the genetic machinery used to copy instructions encoded in DNA as the cell divides and multiplies as part of growth. Viruses invade human cells and use their machinery to copy themselves, but their entry can be blocked by the dense structure of the nucleus.
The new study, led by researchers at NYU Langone Health, found that the herpes simplex virus uses a protein called infectious cell protein 4 (ICP4) to make the human nucleus more fluid, thereby making it easier for the virus to replicate itself. The study, published online March 5 in the journal Molecular Cell, found that inhibiting ICP4’s ability to mobilize the nuclear compartment reduced the rate of production of new viral copies by a factor of four.
The physical state of the nucleus is a fundamental barrier that viruses must overcome in order to multiply. Viruses are masters at manipulating cells, and studying their tricks reveals fundamental laws of biology. ”
Dr. Liam Holt, Senior Research Author; Professor in the Department of Biochemistry and Molecular Pharmacology and Faculty in the Systems Genetics Institute at New York University Langone Health
The research team chose to study herpes simplex virus type 1 because it is one of the most prevalent infections, with a 2025 study estimating that 64 percent of adults worldwide will be infected during their lifetime, many of whom are asymptomatic.
room to build
To multiply, the authors say, viruses need room to build relatively large structures called condensates (dense droplets that concentrate molecules). In the case of HSV-1, the condensate acts as a temporary factory built within the host’s nucleus to mass-produce virus. If there is enough space to move, the small droplets can coalesce into larger droplets, which the researchers believe concentrates the virus’s replication machinery in one place, increasing its efficiency.
The study authors theorize that herpes simplex uses a key process involving structural changes in the human nucleus to create space. There, DNA strands are known to be wrapped around spools of proteins called histones, all within a superstructure called chromatin. In a normal nucleus, the formation of viral condensate factories is hindered by the chromatin network, like trying to inflate a balloon in a tight fishing net.
According to the study authors, ICP4 can prepare the human nucleus for virus replication because it binds to proteins that prepare human cells for transcription, the process by which parts of the genetic code are read by the cell’s machinery to transmit messages. But in order to read the code, the surrounding chromatin must unwind the signal to give the DNA access to the transcription machinery.
Previous studies have shown that ICP4 binds to a group of chromatin remodeling proteins that carry out this unwinding, altering chromatin structure and movement. In this study, only ICP4 was found to increase chromatin movement. Importantly, however, the authors did not observe changes in transcription rate that such movements usually precede.
Therefore, when combined with previous studies, this study suggests that viral ICP4 binds to a protein complex that unwinds DNA around histones, not to allow access to genes, but only to cause unwinding. The researchers say this movement can change the physical properties of chromatin, loosening the interior of the nucleus and increasing the size of viral condensates. They say that ICP4, by itself and independently of other known processes, can efficiently change the properties of infected nuclei to aid virus replication at the very early stages of infection.
To measure the physical properties of the nucleus, the researchers engineered cells to produce glowing protein nanoparticles called nucGEMs. The researchers recorded videos via a microscope to track how far these particles moved as a measure of the thickness of the nuclear environment. When the researchers then infected the cells with herpes simplex virus type 1, the glowing particles bounced back much harder.
We are currently working to confirm the mechanism by which ICP4 fluidizes the nucleus. This could provide new specific targets for physically combating viral replication. We will also investigate whether this mechanism is also used by other viruses that replicate in the nucleus, from the double-stranded DNA virus that causes shingles to RNA viruses like the influenza virus and retroviruses like HIV. ”
Dr. Nora Herzog, first study author, recent graduate of the Biomedical Sciences Program at New York University Langone and currently a postdoctoral fellow at the Parc Citientific, University of Valencia, Valencia, Spain
In addition to Dr. Holt and Dr. Herzog, the authors of the study from NYU Langone are Tong Shu, Gururaj Kidiyoor, Sarah Keegan, Ian Mohr, and Angus Wilson from the Systems Genetics Institute, Department of Microbiology, and Department of Biochemistry and Molecular Pharmacology. Other authors are Farah Corci of Paris Cité University, David Chenoweth of the University of Pennsylvania, and Huaying Zhang of Carnegie Mellon University.
Funding for this research was provided by National Institutes of Health (NIH) grants GM132447, AI176335, AI170583, GM056927, and AI073898. National Science Foundation (NSF) grant MCB-2145083 and Hypothesis Fund.
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Reference magazines:
Duke, New Jersey; others. (2026). Herpes simplex virus 1 fluidizes the nucleus, allowing condensate formation. molecular cell. DOI: 10.1016/j.molcel.2026.02.005. https://www.cell.com/molecular-cell/fulltext/S1097-2765(26)00100-0
