To test the effects of ZIKV on normal adult human neural cells, we inoculated nonmalignant neural tissues from adult epilepsy specimens (
Fig. 3, T–V). ZIKV did not infect normal adult human brain tissues, including NeuN
+ neurons (
Fig. 3, W and Y) and GFAP
+ glial cells (
Fig. 3, X and Z), as limited viral replication was detected compared with glioblastomas (Fig. S2, N and O). In addition, compared with GSCs and DGCs, the human brain neural cell cultures that were derived from epilepsy patients (NM55 and NM177) or from differentiated human neural stem cells (Hu-DNCs) demonstrated limited ZIKV infection (Fig. S2, P–U).
(…)
We recapitulated relevant conditions for human brain tumor therapy using mice. As mice are not natural hosts for ZIKV, pathogenesis studies have used animals with acquired or genetic deficiencies of type I IFN signaling (
Lazear et al., 2016). To overcome this limitation, we used a mouse-adapted ZIKV-Dakar that had gained virulence through passage in a
Rag1−/− host (
Govero et al., 2016;
Sapparapu et al., 2016).
(…)
To. assess the oncolytic effects of ZIKV in vivo, we generated mouse gliomas from two different mouse cell lines (GL261 and CT-2A) grown in syngeneic hosts. Glioma cells were transduced with a luciferase reporter and permitted to form tumors, which were validated by bioluminescence imaging and histopathology (
Fig. 4, C–E). Mice with tumors were randomized into two groups and treated 2 wk after implantation with either PBS control or mouse-adapted ZIKV-Dakar (10
3 focus-forming units [FFU]). Histological examination at 1 wk after tumor treatment demonstrated that the ZIKV-treated tumors were smaller in size compared with PBS-treated tumors (
Fig. 4, F–I).
Notably, ZIKV infection extended the life spans of tumor-bearing mice (
Fig. 4 J). To test whether tumor-bearing mice could benefit from a higher dose of virus, we inoculated 10
5 FFU of the mouse-adapted ZIKV-Dakar at 1 wk after implantation with the GL261 model. The survival time of tumor-bearing mice was greater compared with that of the control or the 10
3-FFU dose (
Fig. 4 K). To determine the specificity of cell targeting, we stained for ZIKV antigen and markers of stem cell proliferation and differentiation (
Fig. 4, L–T). ZIKV infected ∼6% of glioma cells at the endpoint (
Fig. 4 T), with the majority of these cells expressing the precursor marker SOX2 (
Fig. 4, L, M, and T). In contrast, GFAP
+ tumor cells were less infected (
Fig. 4, N and O). Effects on proliferating cell populations were measured by Ki-67 staining and BrdU treatment and staining.
