Pharyngeal motor cortex grey matter abnormalities and retinal photoreceptor layer dysfunction in macaques exposed to Zika virus in utero

Abstract One third of infants who have prenatal Zika virus (ZIKV) exposure and lack significant defects consistent with congenital Zika syndrome (CZS) manifest neurodevelopmental deficits in their second year of life. We hypothesized that prenatal ZIKV exposure would lead to brain abnormalities and neurodevelopmental delays in infant macaques, as measured by quantitative hearing, neurodevelopmental, ocular and brain imaging studies. We inoculated 5 pregnant rhesus macaques with ZIKV during the first trimester, monitored pregnancies with serial ultrasounds, determined plasma viral RNA (vRNA) loads, and evaluated the infants for birth defects and neurodevelopmental deficits during their first week of life. ZIKV-exposed and control infants (n=16) were evaluated with neurobehavioral assessments, ophthalmic examinations, optical coherence tomography, electroretinography with visual evoked potentials, hearing examinations, magnetic resonance imaging (MRI) of the brain, gross post mortem examination, and histopathological and vRNA analyses of approximately 40 tissues and fluids. All 5 dams had ZIKV vRNA in plasma and seroconverted following ZIKV inoculation. One pregnancy resulted in a stillbirth. The ZIKV-exposed infants had decreased cumulative feeding volumes and weight gains compared with control infants, and also had grey matter abnormalities in the pharyngeal motor cortex identified by quantitative voxel-based morphometric comparisons. Quantitative ocular studies identified differences between ZIKV-exposed and control infants in retinal layer thicknesses and electroretinograms that were not identified in qualitative ophthalmic evaluations. Despite these findings of neuropathology, no ZIKV vRNA or IgM was detected in the infants. This suggests that ZIKV exposure without measurable vertical transmission can affect brain development in utero and that subtle neurodevelopmental delays may be detected with quantitative analyses in early infancy. Quantitative brain analyses, such as these, may predict neurodevelopmental delays that manifest later in childhood and allow early intervention and targeted therapies to improve functional outcomes of ZIKV exposed children. Author Summary Human infants with born to women with Zika virus infection during pregnancy are at risk for neurodevelopmental deficits later in childhood. We hypothesized that we could identify brain abnormalities associated with neurodevelopmental deficits in infant macaques exposed to Zika virus during pregnancy. We identified brain and retinal abnormalities in Zika virus-exposed infant macaques during their first week of life, which may be related to their findings of decreased feeding and slower weight gain. None of the infants had direct evidence of Zika virus infection in their tissues, body fluids or by detection of IgM antibodies. This suggests that Zika virus exposure during pregnancy can affect brain development in utero and that quantitative brain imaging analyses may predict neurodevelopmental delays. Early identification of Zika virus-exposed children at risk of neurodevelopmental deficits would promote targeted therapies in this population and improve the functional outcome of all Zika virus exposed children.