Human cytomegalovirus (CMV) infections can cause severe neurological complications, particularly in newborns and immunocompromised patients. Children affected with congenital CMV infection may develop long-term neurological damage and intellectual disabilities. Currently, postnatal antiviral therapies are limited and there are no prenatal options available. Research on antivirals against congenital CMV infections is, at least partly, restricted due to the lack of physiologically relevant models and the use of lab-adapted CMV strains with limited clinical relevance. In this study, we evaluated the toxicity and antiviral efficacy of three FDA-approved anti-CMV drugs against two CMV strains, a clinical and a lab-adapted strain, using two human induced pluripotent stem cell (iPSC-)derived central nervous system models, viz. neural progenitor cells (NPCs) and dorsal forebrain regionalized neural organoids (RNOs). We found iPSC line-dependent differences in antiviral toxicity. We observed that antiviral treatment restored NPCs and RNOs gene expression after CMV infection and reduced CMV copy numbers. Infection of NPCs and RNOs with the clinical CMV strain, but not with the lab-adapted strain, led to an impaired expression of cortical development markers. Our findings highlight the value of using physiologically relevant human models and clinical CMV strains to understand the neuropathogenesis of congenital CMV and to test therapeutic strategies.
Human cytomegalovirus (CMV) is a double-stranded DNA virus belonging to the Betaherpesvirinae subfamily. CMV infections are generally mild but immunocompromised patients and (premature) infants have increased risk of developing severe complications (Fowler et al., 2022). In utero transmission of CMV during pregnancy can cause congenital CMV (cCMV) infection. cCMV remains the leading cause of disease among congenital conditions, affecting 0.5-0.7% of newborns of which 50-75% develop long-term neurological damage or intellectual disabilities (P. D. Griffiths, 2012; Lancini et al., 2014; Rafailidis et al., 2008). Additionally, 15-25% of infected newborns, including those asymptomatic at birth, can experience sensorineural hearing loss later in life (Trevisan et al., 2024).
Antiviral treatment options against CMV are limited and include only letermovir, ganciclovir, and maribavir. Ganciclovir is currently the only recommended postnatal treatment option for cCMV disease (Luck et al., 2017). The FDA approved the use of letermovir and maribavir only for transplant cases, respectively (FDA, 2021; Merck, 2017). Thus, there is an unmet need to evaluate antivirals against cCMV infection, but preclinical antiviral data are limited due to a lack of relevant human model systems and the use of lab-adapted, rather than circulating clinical CMV strains.
To date, animals and immortalised cell lines serve as the standard in pre-clinical CMV antiviral screening but both have several important limitations including the lack of species-specificity and physiological complexity (Lischka et al., 2010; M. S. O’Brien et al., 2018; Piret et al., 2022; Wildum et al., 2015). Therefore, there is an increasing shift towards three-dimensional (3D) human-based organoid models. The potential of human induced pluripotent stem cell (iPSC)-derived neural organoids to model CMV infection has been shown in a small number of studies using lab-adapted CMV strains. These CMV infected organoids have shown alterations in the development of cortical zones, impaired calcium signalling, and signal transduction as well as transcriptional impairments in CMV infected cells (Brown et al., 2019; Ijezie et al., 2023; B. S. O’Brien et al., 2022; Sison et al., 2019; G. Sun et al., 2020).
The second major incumbrance in preclinical CMV studies is the use of lab-adapted CMV strains. Under in vitro conditions, CMV quickly adapts genomic changes, leading to a distinguishable variance between lab-adapted and clinical strains, complicating clinical translation(Murphy et al., 2003; Wilkinson et al., 2015). While bacterial artificial chromosome (BAC)-derived CMV clones maintain genetic stability, they originate from high passage strains with pre-existing genomic alterations (Hahn et al., 2002; O’Connor & Murphy, 2012; Sinzger et al., 2008; Stanton et al., 2010). Using clinical or minimally passaged strains, which represent circulating CMV, alongside relevant human models, holds the most promise for identifying new antivirals (P. Griffiths & Reeves, 2021; Wilkinson et al., 2015).
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