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The role of PD-1\/PD-L1 immune checkpoint in acute ZIKV infection remains to be understood. In this study we demonstrated the activation of PD-1\/PD-L1 immune checkpoint by ZIKV. mRNA and protein expression of PD-L1 was boosted by ZIKV not only in SF268 and JEG3 cell lines but also in human dendritic cells. PD-1 expression was more abundant on CD8<jats:sup>+<\/jats:sup> T cells in ZIKV-infected mice. Elevated PD-L1 expression was also observed in the brain, testis and spleen of ZIKV-infected A129 mice. Blocking PD-L1 effectively inhibited ZIKV infection, reducing viral loads in all tissues. In addition, anti-PD-L1 antibody treatment further increased virus-specific CD8<jats:sup>+<\/jats:sup> T cells, KLRG<jats:sup>+<\/jats:sup> CD8<jats:sup>+<\/jats:sup> T cells, and effector memory CD8<jats:sup>+<\/jats:sup> T cells. PD-L1 blockade also induced interferon \u03b3, granzyme B, and interleukin 2 expression in antigen-specific CD8<jats:sup>+<\/jats:sup> T cells, consistent with activation of these cells. Mechanistically, the induction of PD-L1 expression might be ascribed to viral NS4B protein and its interaction with GRP78. Our findings suggest that targeting the PD-1\/PD-L1 pathway could have antiviral effect against ZIKV.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013457","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T17:57:10Z","timestamp":1757354230000},"page":"e1013457","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Activation of PD-1\/PD-L1 immune checkpoint by Zika virus"],"prefix":"10.1371","volume":"21","author":[{"given":"Chenxi","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubin","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weixin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chon 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