Eyes of 4- to 6-week-old C57BL/6 and ISG15–/– mice (n = 7–10/group) were injected intravitreally with 104 PFU of ZIKV (strain PRVABC59, PR2015). (A) Representative funduscopic images showing the time course of retinal lesion/chorioretinal atrophy and RPE mottling in WT and ISG15–/– mice. (B) Quantification of the percentage area with retinal lesions per eye in WT and ISG15–/– mice at indicated time points (24, 48, 72, and 96 hours) using ImageJ analysis (mean ± SD; *P < 0.05, ***P < 0.0005; Student’s t test). (C) qRT PCR showing intracellular viral RNA quantification in WT and ISG15–/– mouse retinas at various time points (mean ± SD; *P < 0.05, **P < 0.005; Student’s t test). (D) Representative images showing TUNEL-positive cells (green, indicated by the red arrows) and DAPI (blue) in various layers of the retinas of ZIKV-infected eyes (96 hours) and mock treatment. ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer. Original magnification, × 20.