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J Virol. 2017 Oct 4. pii: JVI.01469-17. doi: 10.1128/JVI.01469-17. [Epub ahead of print]

Prior Dengue virus exposure shapes T cell immunity to Zika virus in humans.

Author information

1
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA.
2
Genetech Research Institute, Colombo, Sri Lanka.
3
Department of Pathology, University of Miami Miller School of Medicine, Miami, FL.
4
Division of Clinical Immunology and Allergy, School of Medicine, University of São Paulo, Brazil.
5
Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
6
Federal University of the State of Rio de Janeiro (UNIRIO).
7
Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
8
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC.
9
Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.
10
University of Vermont, School of Medicine, Burlington, VT.
11
National Virology Laboratory, National Center for Diagnosis and Reference, Ministry of Health, Managua, Nicaragua.
12
Health Center Sócrates Flores Vivas, Ministry of Health, Managua, Nicaragua.
13
Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, USA.
14
Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN.
15
Blood Systems Research Institute, San Francisco, CA.
16
Instituto de Investigaciones Medico-Biologicas, Universidad Veracruzana, Veracruz, Mexico.
17
Vaccine Research Center, NIAID, NIH, Bethesda, MD.
18
Centre for Global Vaccine Research, Institute of Infection and Global Health, University of Liverpool, 8 West Derby Street, Liverpool, L69 7BE, UK.
19
NIHR Health Protection Research Unit for Emerging and Zoonotic Infections, University of Liverpool, 8 West Derby Street, Liverpool, L69 7BE, UK.
20
Tropical & Infectious Disease Unit, Royal Liverpool University Hospital, Liverpool, L7 8XP, UK.
21
Institute of Infection and Global Health, University of Liverpool, 8 West Derby Street, Liverpool, L69 7BE, UK.
22
Walton Centre NHS Foundation Trust, Liverpool, L9 7LJ, UK.
23
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA alex@lji.org.

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.IMPORTANCE The issue of potential ZIKV and DENV cross-reactivity and how pre-existing DENV T cell immunity modulates ZIKA T cell responses is of great relevance as the two viruses often co-circulate and ZIKA virus has been spreading in geographical regions where DENV is endemic or hyper-endemic. 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 towards important implications for vaccine design against this global threat.

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