Prior Dengue Virus Exposure Shapes T Cell Immunity to Zika Virus in Humans - Journal of Virology

1. Alba Grifoni^a,
2. John Pham^a,
3. John Sidney^a,
4. Patrick H. O'Rourke^a,
5. Sinu Paul^a,
6. Bjoern Peters^a,
7. Sheridan R. Martini^a,
8. Aruna D. de Silva^a,^b,
9. Michael J. Ricciardi^c,
10. Diogo M. Magnani^c,
11. Cassia G. T. Silveira^d,
12. Alvino Maestri^d,
13. Priscilla R. Costa^d,
14. Luzia Maria de-Oliveira-Pinto^e,
15. Elzinandes Leal de Azeredo^e,
16. Paulo Vieira Damasco^f,
17. Elizabeth Phillips^g,^w,
18. Simon Mallal^g,^w,
19. Aravinda M. de Silva^h,
20. Matthew Collins^h,
21. Anna Durbinⁱ,
22. Sean A. Diehl^j,
23. Cristhiam Cerpas^k,
24. Angel Balmaseda^k,
25. Guillermina Kuan^l,
26. Josefina Coloma^m,
27. Eva Harris^m,
28. James E. Crowe Jr.ⁿ,
29. Mars Stone^o,
30. Phillip J. Norris^o,
31. Michael Busch^o,
32. Hector Vivanco-Cid^p,
33. Josephine Cox^q,
34. Barney S. Graham^q,
35. Julie E. Ledgerwood^q,
36. Lance Turtle^r,^s,^t,
37. Tom Solomon^s,^u,^v,
38. Esper G. Kallas^d,
39. David I. Watkins^c,
40. Daniela Weiskopf^a and
41. Alessandro Sette^a

1. ^aDivision of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA
2. ^bGenetech Research Institute, Colombo, Sri Lanka
3. ^cDepartment of Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA
4. ^dDivision of Clinical Immunology and Allergy, School of Medicine, University of São Paulo, São Paulo, Brazil
5. ^eFundação Oswaldo Cruz, Rio de Janeiro, Brazil
6. ^fFederal University of the State of Rio de Janeiro (UNIRIO), Rio de Janeiro, Brazil
7. ^gDepartment of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
8. ^hDepartment of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
9. ⁱJohns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
10. ^jUniversity of Vermont, School of Medicine, Burlington, Vermont, USA
11. ^kNational Virology Laboratory, National Center for Diagnosis and Reference, Ministry of Health, Managua, Nicaragua
12. ^lHealth Center Sócrates Flores Vivas, Ministry of Health, Managua, Nicaragua
13. ^mDivision of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, California, USA
14. ⁿVanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA
15. ^oBlood Systems Research Institute, San Francisco, California, USA
16. ^pInstituto de Investigaciones Medico-Biologicas, Universidad Veracruzana, Veracruz, Mexico
17. ^qVaccine Research Center, NIAID, NIH, Bethesda, Maryland, USA
18. ^rCentre for Global Vaccine Research, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom
19. ^sNIHR Health Protection Research Unit for Emerging and Zoonotic Infections, University of Liverpool, Liverpool, United Kingdom
20. ^tTropical & Infectious Disease Unit, Royal Liverpool University Hospital, Liverpool, United Kingdom
21. ^uInstitute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom
22. ^vWalton Centre NHS Foundation Trust, Liverpool, United Kingdom
23. ^wInstitute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia

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 preexisting 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-preexposed 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 from DENV-preexposed donors selectively upregulated granzyme B and PD1, unlike DENV-naive 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.

IMPORTANCE The issue of potential ZIKV and DENV cross-reactivity and how preexisting DENV T cell immunity modulates Zika T cell responses is of great relevance, as the two viruses often cocirculate and Zika virus has been spreading in geographical regions where DENV is endemic or hyperendemic. Our data show that memory T cell responses elicited by prior infection with DENV recognize ZIKV-derived peptides and that DENV exposure prior to ZIKV infection influences the timing, magnitude, and quality of the T cell response. Additionally, we show that ZIKV-specific responses target different proteins than DENV-specific responses, pointing toward important implications for vaccine design against this global threat.

KEYWORDS

FOOTNOTES

• • Received 25 August 2017.
  • Accepted 20 September 2017.
  • Accepted manuscript posted online 4 October 2017.
• Address correspondence to Alessandro Sette, alex{at}lji.org.

• Citation Grifoni A, Pham J, Sidney J, O'Rourke PH, Paul S, Peters B, Martini SR, de Silva AD, Ricciardi MJ, Magnani DM, Silveira CGT, Maestri A, Costa PR, de-Oliveira-Pinto LM, de Azeredo EL, Damasco PV, Phillips E, Mallal S, de Silva AM, Collins M, Durbin A, Diehl SA, Cerpas C, Balmaseda A, Kuan G, Coloma J, Harris E, Crowe JE, Jr, Stone M, Norris PJ, Busch M, Vivanco-Cid H, Cox J, Graham BS, Ledgerwood JE, Turtle L, Solomon T, Kallas EG, Watkins DI, Weiskopf D, Sette A. 2017. Prior dengue virus exposure shapes T cell immunity to Zika virus in humans. J Virol 91:e01469-17. http://ift.tt/2jzUtQp.

• Supplemental material for this article may be found at http://ift.tt/2jzUtQp.

• Copyright © 2017 American Society for Microbiology.

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