Letermovir shows antiviral and neuroprotective effects in differentiating neurons and cerebral organoids mimicking...

Human cytomegalovirus (HCMV) is the leading viral cause of congenital defects. The triggers of viral neuropathogenesis during congenital infection (cCMV) are still unclear, and treatment options are limited. We used both a two-dimensional model of dynamic neurogenesis and cerebral organoids (COs), recapitulating the developing brain in the first trimester of gestation, to investigate the neuropathogenesis induced by HCMV. We also evaluated antiviral and neuroprotective effects of different compounds, both approved, direct-acting drugs and investigational, host-directed antivirals. In differentiating neurons, treatment with direct-acting antivirals blocked HCMV active replication and provided some protection from virus-induced defects. COs exposed to two different strains of HCMV showed viral spread throughout the organoids, dysregulation of key players of neurogenesis, alteration of the tissue cytoarchitecture, and triggering of innate antiviral and pro-inflammatory responses. Inter-strain differences in virus release and growth attenuation were detected in infected COs. Regardless of the strain, treatment with direct-acting antivirals, particularly letermovir, completely abolished HCMV replication, protected COs from virus-induced disorganization of tissue architecture, and dampened innate immune and pro-inflammatory response activation. Importantly, we also demonstrated the efficacy of the antiviral treatment in HCMV-infected COs in blocking an already established infection. This study contributes to shed light on HCMV-induced neuropathogenesis that occurs during congenital infection. Importantly, we demonstrated the neuroprotective effects of letermovir in models of human developing brain, holding promise for its evaluation as a candidate therapeutic agent to ameliorate cCMV-associated neurodevelopmental defects.