Journal of Virology, October 2017
Alba Grifoni, John Pham, John Sidney, Patrick H. O’Rourke, Sinu Paul, Bjoern Peters, Sheridan R. Martini, Aruna D. de Silva, Michael J. Ricciardi, Diogo M. Magnani, Cassia G. T. Silveira, Alvino Maestri, Priscilla R. Costa, Luzia Maria de-Oliveira-Pinto, Elzinandes Leal de Azeredo, Paulo Vieira Damasco, Elizabeth Phillips, Simon Mallal, Aravinda M. de Silva, Matthew Collins, Anna Durbin, Sean A. Diehl, Cristhiam Cerpas, Angel Balmaseda, Guillermina Kuan, Josefina Coloma, Eva Harris, James E. Crowe, Jr., Mars Stone, Phillip J. Norris, Michael Busch, Hector Vivanco-Cid, Josephine Cox, Barney S. Graham, Julie E. Ledgerwood, Lance Turtle, Tom Solomon, Esper G. Kallas, David I. Watkins, Daniela Weiskopf, Alessandro Sette
Abstract
While progress has been made in characterizing humoral immunity to Zika virus (ZIKV) in humans, little is known regarding the corresponding T cell responses to ZIKV. Here we investigate the kinetics and viral epitopes targeted by T cells responding to ZIKV and address the critical question of whether pre-existing dengue virus (DENV) T cell immunity modulates these responses. We find that memory T cell responses elicited by prior infection with DENV or vaccination with Tetravalent Dengue Attenuated Vaccines (TDLAV) recognize ZIKV-derived peptides. This cross- reactivity is explained by the sequence similarity of the two viruses, as the ZIKV peptides recognized by DENV-elicited memory T cells are identical or highly conserved in DENV and ZIKV. DENV exposure prior to ZIKV infection also influences the timing and magnitude of the T cell response. ZIKV-reactive T cells in the acute phase of infection are detected earlier and in greater magnitude in DENV-immune patients. Conversely, the frequency of ZIKV-reactive T cells continues to rise in the convalescent phase in DENV-naive donors, but declines in DENV pre-exposed donors, compatible with more efficient control of ZIKV replication and/or clearance of ZIKV antigen. The quality of responses is also influenced by previous DENV exposure, and ZIKV-specific CD8 T cells form DENV pre-exposed donors selectively up-regulated granzyme B and PD1, as compared to DENV-naïve donors. Finally, we discovered that ZIKV structural proteins (E, prM and C) are major targets of both the CD4 and CD8 T cell responses, whereas DENV T cell epitopes are found primarily in nonstructural proteins.