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

Human cytomegalovirus (HCMV) is the leading cause of congenital viral infections, frequently accompained with long-term neurological sequelae in children. The cell types and mechanisms involved in establishing lifelong CMV latency in brain, from which the virus reactivates intermittently, remain enigmatic. Infection of newborn mice with mouse CMV (MCMV) closely mimicks the pathophysiology of congenital HCMV and was used to unravel the factors involved in CMV infection of the central nervous system (CNS). Here we show that cortex and hippocampus are major sites of productive MCMV infection during the acute phase in newborn mice. Infectious virus was first produced by astrocytes, then microglia, and finally by neurons, which were the major sites of viral replication during the late phase of infection. CD4 ⁺ T-cells were pivotal in resolving a productive infection in neurons in an interferon-gamma (IFN-γ)-dependent manner. IFN-γ can also suppress HCMV infection of human neuronal cell line and neurons in human fetal brain organotypic tissue culture. Finally, we show that MCMV establishes latency in neurons and that CD4 ⁺ T-cells are crucial to prevent virus reactivation. This study has important translational potential as it demonstrates that boosting CD4 ⁺ T-cell mediated immunity could prevent neurological sequelae following congenital CMV infection.