The term "virokine" was coined by National Institutes of Health virologist Bernard Moss. The early 1990s saw several reports of virally encoded proteins with sequence homology to immune proteins, followed by reports of the cowpox and vaccinia viruses directly interfering with key immune regulator IL1B. The first identified virokine was an epidermal growth factor-like protein found in myxoma viruses.
Much of the early work on virokines involved vaccinia virus, which was discovered to secrete proteins that promote proliferation of neighboring cells and block complement immune activity leading to inflammation.