Dr. Alex Evilevitch of Carnegie Mellon University and his colleagues provide the first experimental evidence of a high internal pressure of tens of atmospheres within Herpes simplex virus 1, resulting from the confined genome. NPC – nuclear pore complex. The study provides the first experimental evidence of high internal pressure within a virus that infects humans – a phenomenon previously only attributed to viruses that infect bacteria.
“Despite billions of years of evolution separating eukaryotic viruses and bacteriophages, the existence of an internal pressure capable of powering the ejection of DNA into a host cell has been conserved. This suggests that it is a key mechanism for viral infection across organisms and presents us with a new drug target for antiviral therapies,” said Dr. Evilevitch.
Many viruses, whether they infect bacteria, plants or animals, are adept at packing long stretches of DNA or RNA within their nanometer-sized protein shells. Herpes simplex virus 1 (HSV-1) contains double-stranded DNA that is 400 times longer than the radius of the viral shell it fills.
The DNA gets packaged so tightly that it bends upon itself, resulting in repulsive forces that exert tremendous energy and pressure on the virus’s outer shell. When HSV-1 infects a cell, it enters through the outer cell membrane and makes its way to the cell nucleus, where it docks in a small hole found in the nuclear membrane. That act is like a key opening a lock that allows the HSV-1 to eject its DNA into the cell nucleus.
For years, scientists hypothesized that a high internal pressure inside eukaryotic viruses like HSV-1 enabled the virus to shoot its DNA into the host cell’s nucleus. But it was impossible to measure HSV-1′s internal pressure without knowing how to release the viral DNA in a controlled, experimental setting.
Dr. Evilevitch’s colleagues Prof. William Newcomb and Prof. Jay Brown from the University of Virginia’s School of Medicine discovered a protein called UL6 that, when degraded, caused DNA to exit the virus. In their experiments, they degraded UL6, which triggered HSV-1 to eject its DNA. At the same time, they applied an external force to the virus and monitored how much DNA was released. When the external pressure reached tens of atmospheres, HSV-1 didn’t release any DNA, indicating that the internal and external pressure were equal.
“This measurement of high internal pressure – tens of atmospheres – within a human virus is a fundamentally important discovery of the physical-chemical mechanism of eukaryotic viral infection,” Dr. Evilevitch said.
The mechanism of pressurized infection found in HSV-1 is applicable to any of the eight known Herpes viruses that cause disease in humans, including Varicella zoster virus, which causes chickenpox in children and shingles in adults, and the Epstein-Barr virus, which causes mononucleosis and is associated with several types of cancer, such as Hodgkin’s lymphoma.