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Primate simplexviruses are closely related neurotropic herpesviruses, which are largely apathogenic in their respective host species. However, cross-species transmission of Macacine alphaherpesvirus 1 (McHV1, also termed herpes B virus) from rhesus macaques to humans can cause fatal encephalomyelitis. In contrast, closely related viruses, such as Cercopithecine alphaherpesvirus 2 (CeHV2, also termed simian agent 8) or Papiine alphaherpesvirus 2 (PaHV2, also termed herpesvirus papio 2), have not been linked to human disease and are believed to be largely apathogenic in humans. Here, we investigated whether McHV1, PaHV2 and CeHV2 differ in their capacity to infect human and non-human primate (NHP) cells. For comparison, we included the human simplexviruses HSV1 and HSV2 in our analyses. All five viruses replicated efficiently in cell lines of human and African green monkey origin, and McHV1 and PaHV2 also showed robust replication in rhesus macaque cell lines. In contrast, the replication of CeHV2 and particularly HSV1 and HSV2 in cell lines of rhesus macaque origin were reduced or inefficient. Similarly, McHV1, but not CeHV2, efficiently infected rhesus macaque brain organoids. These results point towards the previously unappreciated partial resistance of certain rhesus macaque cells to HSV1/HSV2/CeHV2 infection and reveal similarities between the cell tropism of McHV1 and PaHV2 that might be relevant for risk assessment.
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