A cellular threshold determines whether herpesviruses become active or remain dormant, according to a study published in Nature Communications. Researchers from the laboratory of Noam Stern-Ginossar at the Weizmann Institute of Science found that whether a virus becomes active or stays dormant in a cell depends on how many viral particles, or virions, enter the cell. This discovery could lead to new therapies that control how the infection progresses. Herpesviruses, including human cytomegalovirus (HCMV), can enter a dormant state inside cells, reactivating when conditions are favorable. HCMV infects most people in the world, usually without causing symptoms, but can cause serious illness in individuals with weakened immune systems. It can also be passed from a mother to her fetus during pregnancy, potentially leading to developmental issues and hearing loss. Monocytes, a type of white blood cell, are known to carry dormant HCMV, while macrophages — which monocytes can turn into — are more likely to experience active infection. In the study, led by doctoral student Yaarit Kitsberg and supervised by Stern-Ginossar and Dr. Michal Schwartz, the researchers compared gene expression in human monocytes and macrophages. They found that monocytes didn’t overproduce proteins involved in DNA compaction, which had previously been thought to influence infection outcomes. Instead, they discovered that macrophages overexpress surface proteins that viruses use to enter cells. This suggests that the infection’s outcome may be determined right at the moment the virus enters the cell. The researchers labeled virions with fluorescent markers and observed that more virions entered macrophages than monocytes. When they genetically modified monocytes to have more efficient HCMV receptors, the number of virions entering the cells increased 15 times on average, and the rate of active infection rose sharply. This suggests that different cell types require different minimum numbers of virions to trigger an active infection. The study also identified a specific cell-surface protein on macrophages that, when removed, significantly reduced the rate of active infection. However, adding this protein to monocytes did not increase their infection rate, suggesting that other surface proteins might be involved. This research could aid in developing vaccines against HCMV, as many vaccines target the way viruses bind to cell surface proteins. In a follow-up study published in Proceedings of the National Academy of Sciences, the researchers looked at the role of "immediate-early" proteins in active infection. These proteins are produced early after a virus enters a cell and start a chain of events that lead to active infection. The study found that these proteins do two important things: they break down structures in the cell that try to compact and neutralize the virus’s genetic material, and they prompt the cell to prepare the necessary building blocks for DNA replication, making them available to the virus. These actions help the virus overcome the cell's defenses and start an active infection.