Neuron-restricted cytomegalovirus latency in the central nervous system regulated by CD4⁺ T-cells and IFN-γ

All human herpesviruses establish latency following the resolution of the primary infection. Among these, alpha-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 beta-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. 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.© 2025. The Author(s).

Croatian Acad Sci & Arts
Univ Freiburg
Univ Rijeka
Erasmus MC
Helmholtz-Zentrum für Infektionsforschung GmbH
Veterinärmedizinische Universität Wien
University of Rijeka
Croatian Academy of Sciences & Arts
Erasmus University Rotterdam
University of Freiburg
Helmholtz Association
Medizinische Hochschule Hannover