Herpes simplex viruses infect both humans (e.g., herpes simplex virus 1, HSV-1) and non-human primates and are well adapted to their respective natural hosts. As a result, they usually cause no or only mild symptoms in their natural hosts; generalized infections and severe illness are very rare. However, when these viruses are transmitted to a non-natural host (e.g., from monkeys to humans), severe disease can occur.

Transmission of the herpes B virus (Macacine alphaherpesvirus 1, McHV-1) from rhesus monkeys to humans can have serious consequences: affected individuals can develop encephalomyelitis (inflammation of the brain and spinal cord), which is fatal in about 70–80% of untreated cases. To date, approximately 50 cases have been documented, of which at least 20 were fatal. The risk of a fatal outcome can be reduced with the early administration of antiviral medication (e.g., valacyclovir, ganciclovir). It was previously thought that infection always leads to disease, indicating an acute, non-latent course. However, it was recently reported that a person died of virus-induced encephalomyelitis several decades after exposure to herpes B virus, suggesting that latent infection in humans is also possible.

In contrast to herpes B virus, there is no evidence that closely related simplex viruses from baboons (Papiine alphaherpesvirus 2, PaHV-2) or African green monkeys (Cercopithecine alphaherpesvirus 2, CeHV-2) pose a risk to humans, although exposure likely occurs in the wild and in scientific settings. Thus, CeHV-2 and PaHV-2 are likely attenuated as compared to McHV-1, despite their genomes sharing more than 90% sequence similarity with the McHV-1 genome. Therefore, these viruses can be used as research tools to identify the genetic determinants responsible for the high neurovirulence of McHV-1 and to understand the mechanisms underlying the high pathogenic potential of this virus.