Herpes simplex virus 1 (HSV-1) has been found to alter the physical properties of human cell nuclei to facilitate its own replication, according to new research led by scientists at NYU Langone Health. The study, published in Molecular Cell on March 5, details how HSV-1 uses a protein called infected cell protein 4 (ICP4) to make the nucleus more fluid-like, which enables the virus to multiply more efficiently.
The human cell nucleus contains genetic material tightly packed in a gel-like structure. This dense environment can impede viruses that invade cells and attempt to use their machinery for reproduction. The research team discovered that ICP4 changes this environment by increasing the motion of chromatin—the network of DNA and proteins inside the nucleus—making it easier for viral components to move and assemble.
"Blocking the ability of ICP4 to fluidize the nuclear compartment caused a four-fold drop in the production rate of new viral copies," said researchers from NYU Langone Health.
HSV-1 is one of the most common infectious diseases worldwide. A recent estimate suggests that about 64 percent of adults globally are infected with HSV-1 for life, often without symptoms.
Viruses like HSV-1 require space within host cells to build condensates—droplets that gather molecules needed for viral replication. In normal conditions, these condensates are limited by chromatin's tight structure, similar to trying to inflate a balloon inside a net. The study shows that ICP4 interacts with proteins responsible for unwinding DNA from histones, leading not necessarily to increased gene activity but rather making room for larger condensates and thus aiding viral assembly.
Previous studies had shown ICP4's role in attaching to chromatin remodeling proteins. The current findings indicate that while ICP4 increases chromatin motion, it does not accelerate transcription rates as might be expected if gene activation were its primary function.
"Viral ICP4 attaches to the protein complexes that unwind DNA around histones, not to enable access to genes, but just to cause the unwinding," according to the authors. "This motion changes chromatin's physical properties, loosening the nuclear interior."
To assess these changes, researchers engineered cells with glowing nanoparticles called nucGEMs and observed their movement under microscopes before and after infection with HSV-1. They noted significantly increased movement after infection, supporting their conclusions about nuclear softening.
The study involved contributions from multiple institutions including Université Paris Cité, University of Pennsylvania, and Carnegie Mellon University. Funding was provided by several National Institutes of Health grants as well as support from the National Science Foundation and Hypothesis Fund.
