**5. Conclusions**

Since the beginning of the South American ZIKV outbreak, significant research has been conducted to further our understanding of T cell responses to ZIKV infection. In both humans and mouse models of infection, ZIKV induces robust T cell activation, which leads to the establishment of a memory T cell population, suggesting an important role for CD4 and CD8 T cells in the immune response to ZIKV. This is highlighted by depletion studies, in which loss of either CD4, CD8, or both T cell subsets together can result in worsened morbidity, mortality, or even fetal resorption. Identification of ZIKV epitopes, in particular broadly conserved epitopes between studies, and even among *flaviviruses*, could provide novel candidates for vaccine design. Given that the work done so far studying T cell cross-reactivity has demonstrated a protective role for these cells, it stands to reason that cross-reactive epitopes could be useful in vaccination against multiple, co-circulating *flaviviruses*. However, this remains to be formally tested, and the magnitude of the South and Central American ZIKV outbreak in a DENV endemic region suggests that prior DENV immunity may not provide complete protection. Finally, there may be a role for CD8 T cells in enhancing ZIKV pathogenesis, although thus far studies have been completed uniquely in extremely young or immunocompromised mice, raising questions as to whether CD8 T cells also play a role in ZIKV pathogenesis in healthy, immunocompetent adults. In the future, it will be of importance to continue to explore the impact of prior immunity to *flaviviruses* during pregnancy. Further research is also needed to understand whether ZIKV has improved its capacity to evade host immune responses, including T cell-mediated immunity, and whether this has contributed to the increased pathogenesis observed during recent outbreaks.

**Author Contributions:** Conceptualization, R.D.P. and M.J.R.; resources, M.J.R.; writing—original draft preparation, R.D.P.; writing—review and editing, R.D.P. and M.J.R.; visualization, R.D.P. and M.J.R.; supervision, M.J.R.; project administration, M.J.R.; funding acquisition, M.J.R.

**Funding:** The Richer Lab is funded by the Canadian Institutes of Health Research, gran<sup>t</sup> number PJT-152903 and PJT-162212; the Natural Sciences and Engineering Research Council, gran<sup>t</sup> number RGPIN-2016-04713; Fonds de Recherche du Québec—Santé, gran<sup>t</sup> number 32807; and the Canada Foundation for Innovation. R.D.P is supported by the Frederick Banting and Charles Best Canada Graduate Scholarships—Doctoral Award from the Canadian Institutes of Health Research.

**Acknowledgments:** We would like to thank Stephanie Condotta, Marilena Gentile, and Stefanie Valbon for critical review of the manuscript.

**Conflicts of Interest:** The authors declare no conflict of interest.
