2025 Journal of Neuroinflammation Copyright © 2025, The Author(s) open access doi:10.1186/s12974-025-03422-6 BMC Text Wissenschaftlicher Artikel http://creativecommons.org/licenses/by-nc-nd/4.0/ All human herpesviruses establish latency following the resolution of the primary infection. Among these, α-herpesviruses HSV-1, HSV-2 and VZV establish latency in neurons, whereas neurons are not traditionally considered a site of latency for other herpesviruses. Using a combination of in vivo murine models and ex vivo human fetal tissues, we discovered that cytomegalovirus (CMV), a ubiquitous β-herpesvirus, can persist in neurons and that CD4+ T-cell-derived interferon-gamma is critical in restricting active viral replication in this cell type. Furthermore, we show that mouse CMV can establish latency in neurons and that CD4+ T-cells are essential in preventing viral reactivation. Our findings may have translational significance because human cytomegalovirus (HCMV) is the leading cause of congenital viral infections resulting in neurodevelopmental and neuroinflammatory lesions with long-term functional sequelae. Animals Mice Virus Latency Physiology Cytomegalovirus Physiology Cytomegalovirus Immunology CD4-Positive T-Lymphocytes Virology CD4-Positive T-Lymphocytes Immunology Interferon-gamma Metabolism Humans Neurons Virology Neurons Metabolism Mice, Inbred C57BL Central Nervous System Virology Central Nervous System Immunology Cytomegalovirus Infections Immunology Fran Krstanović Andrea Mihalić Ahmad Seyar Rashidi Katarzyna M. Sitnik Zsolt Ruzsics Luka Čičin-Šain Georges M. G. M. Verjans Stipan Jonjić Ilija Brizić Testo Articolo di rivista Text journal article application/pdf eng Neuron-restricted cytomegalovirus latency in the central nervous system regulated by CD4+ T-cells and IFN-γ https://phaidra.vetmeduni.ac.at/o:4067