Ausderau, K. K.; Boerigter, B.; Razo, E. R.; Gutkes, J.; Krabbe, N. P.; Mitzey, A. M.; Walsh, S.; Menna, V.; Drew, J. R.; Kabakov, S.; Eckes, F.; Spanton, R. V.; Shah, A.; Sun, A.; Katz, A.; Kim, C.; Hartman, A.; Weiler, A. M.; Rasmussen, C.; Nork, M.; Basu, P.; Simmons, H. A.; Ver Hoeve, J.; Capuano, S.; Friedrich, T. C.; Mohr, E. L.

Prenatal exposure to Zika virus (ZIKV) results in a spectrum of outcomes, ranging from severe birth defects and early childhood developmental delays to no apparent deficits. However, the mechanisms underlying these outcomes, particularly in the context of different maternal infection conditions, remain poorly defined. In this study, we employed a translational rhesus macaque model of prenatal ZIKV infection to evaluate longitudinal visual and auditory development from 1 to 12 months of age and characterize neurodevelopmental outcomes at 12 months. Pregnant macaques, either flavivirus-naive or with prior dengue virus (DENV) exposure, were inoculated in the first trimester (~30 or 45 gestational days) with an Asian or African lineage of ZIKV or received a saline injection as controls. Maternal plasma viremia duration, viral RNA burden at the maternal-fetal interface, and neutralizing antibody titers did not differ between inoculation cohorts or controls. At 12 months, ZIKV-exposed infants demonstrated altered maternal attachment behaviors and reduced inhibition when approaching sensory stimuli compared to controls. Visual pathway function, assessed by electrophysiology, was significantly impaired at 3 months but normalized by 12 months. Hearing loss was more common among ZIKV-exposed infants, although not statistically significant. Developmental outcomes were associated with prenatal ZIKV exposure itself, independent of viremia duration, neutralizing antibody titer, viral lineage, or maternal DENV immunity, and were not mediated by visual impairment or hearing loss. These findings highlight that any prenatal ZIKV exposure can disrupt early neurobehavioral development and visual function, underscoring the need for prevention strategies focused on maternal infection and early intervention.