Human neural progenitor cell models to study the antiviral effects and neuroprotective potential of approved and investigational human cytomegalovirus inhibitors

Abstract

Human cytomegalovirus (HCMV) is the viral leading cause of congenital defects in newborns worldwide. Many aspects of congenital CMV (cCMV) infection, which currently lacks a specific treatment, as well as the main determinants of neuropathogenesis in the developing brain during HCMV infection are unclear. In this study, we modeled HCMV infection at different stages of neural development. Moreover, we evaluated the effects of both approved and investigational anti-HCMV drugs on viral replication and gene expression in two different neural progenitor cell lines, i.e., human embryonic stem cells-derived neural stem cells (NSCs) and fetus-derived neuroepithelial stem (NES) cells. Ganciclovir, letermovir, nitazoxanide, and the ozonide OZ418 reduced viral DNA synthesis and the production of infectious virus in both lines of neural progenitors. HCMV infection dysregulated the expression of genes that either are markers of neural progenitors, such as SOX2, NESTIN, PAX-6, or play a role in neurogenesis, such as Doublecortin. Treatment with antiviral drugs had different effects on HCMV-induced dysregulation of the genes under investigation. This study contributes to the understanding of the molecular mechanisms of cCMV neuropathogenesis and paves the way for further consideration of anti-HCMV drugs as candidate therapeutic agents for the amelioration of cCMV-associated neurological manifestations.

Keywords: Antiviral drugs; Congenital human cytomegalovirus infection; Neural/stem progenitor cells; Neurogenesis; Neuropathogenesis model.