Prior Dengue Virus Exposure Shapes T Cell Immunity to Zika Virus in Humans

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

Time elapsed between Zika and dengue virus infections affects antibody and T cell responses

“…We found that animals with a midconvalescence to ZIKV developed an early activation of CD4 + and CD8 + effector memory T cells after DENV infection. This early activation has been observed for the opposite scenario in DENVimmune ZIKV-infected patients 24 . Interestingly, the ZIKV early-convalescent group display a modest activation (T-CM>T-EM) early after DENV infection.…”

“…However, recent results from our group and others have shown that previous flavivirus exposure-including DENV-may have no detrimental impact on ZIKV infection in vivo in non-human primates (NHP) 17,18 and humans 19 . Moreover, these studies and others suggest that previous DENV immunity may play a protective role during ZIKV infection involving humoral and cellular responses [20][21][22][23][24] . On the other hand, little is known about the opposite scenario, the role of a previous ZIKV exposure on a subsequent DENV infection, which is relevant to anticipate the dynamics of forthcoming DENV epidemics.…”

“…Early studies of T cells associate their contribution towards immunopathogenesis in DENV secondary infections explained by the original antigenic sin 59 , but increasing evidence suggest their protective role during primary and secondary DENV infections 60 . Recently, with the introduction of ZIKV into The Americas, T cells from DENV immunity are being implicated in mediating cross-protection against ZIKV [22][23][24] . However, the role and kinetics of T cells from ZIKV immunity in a subsequent DENV infection remains unknown.…”

“…Previous studies have demonstrated that DENV and ZIKV specific CD4 + and CD8 + T cells are enriched in certain memory subsets 24,48 . Thus, we measured whether the early activation of T cell subpopulations, such as effector memory (CD3 + CD4 + CD28 -CD95 + ) and central memory (CD3 + CD4 + CD28 + CD95 + ) T cells (T-EM and T-CM), within each T cell compartment was modulated following DENV infection in presence or absence of convalescence to ZIKV (Fig.…”

Zika Vaccine Development: Current Status

“…63,64 In contrast, for ZIKV, CD4 þ and CD8 þ T-cell epitopes have also been found in the prM, C, and E proteins. 65 This has also been observed for Japanese encephalitis virus. 66 In a mouse model, both vaginal and subcutaneous infection with ZIKV led to the proliferation of virus-specific T cells.…”