Abstract
ABSTRACTThe mosquito-borne Zika virus (ZIKV) has spread rapidly into regions where dengue virus (DENV) is endemic, and flavivirus cross-reactive T cell responses have been observed repeatedly in animal models and in humans. Preexisting cellular immunity to DENV is thought to contribute to protection in subsequent ZIKV infection, but the epitope targets of cross-reactive T cell responses have not been comprehensively identified. Using human blood samples from the regions of Nicaragua and Sri Lanka where DENV is endemic that were collected before the global spread of ZIKV in 2016, we employed an in vitro expansion strategy to map ZIKV T cell epitopes in ZIKV-unexposed, DENV-seropositive donors. We identified 93 epitopes across the ZIKV proteome, and we observed patterns of immunodominance that were dependent on antigen size and sequence identity to DENV. We confirmed the immunogenicity of these epitopes through a computational HLA binding analysis, and we showed that cross-reactive T cells specifically recognize ZIKV peptides homologous to DENV sequences. We also found that these CD4 responses were derived from the memory T cell compartment. These data have implications for understanding the dynamics of flavivirus-specific T cell immunity in areas of endemicity.IMPORTANCE Multiple flaviviruses, including Zika virus (ZIKV) and the four serotypes of dengue virus (DENV), are prevalent in the same large tropical and equatorial areas, which are inhabited by hundreds of millions of people. The interplay of DENV and ZIKV infection is especially relevant, as these two viruses are endemic in largely overlapping regions, have significant sequence similarity, and share the same arthropod vector. Here, we define the targets of preexisting immunity to ZIKV in unexposed subjects in areas where dengue is endemic. We demonstrate that preexisting immunity to DENV could shape ZIKV-specific responses, and DENV-ZIKV cross-reactive T cell populations can be expanded by stimulation with ZIKV peptides. The issue of potential ZIKV and DENV cross-reactivity is of relevance for understanding patterns of natural immunity, as well as for the development of diagnostic tests and vaccines.
Highlights
CD4 responses resulting from natural dengue virus (DENV) infection [10] and similar to the strategy we used more recently to map the repertoire of CD4 responses to SARS-CoV-2 in unexposed donors [7]
To address whether the CD4 responses to Zika virus (ZIKV) in DENV-exposed donors could be attributed to responding memory cells, we analyzed expression of the phenotypic markers CD45RA and CCR7 in AIM1 cells following stimulation with ZIKV and DENV peptides (Fig. 9A)
We found that the majority of AIM1 cells showed an effector memory phenotype (TEM; CD45RA2 CCR72), followed by central memory (TCM; CD45RA2 CCR71) (Fig. 9B)
Summary
Among the ZIKV peptides that were associated with the greatest response magnitude (.2,500 SFCs/106 cells), we noticed that 11/12 were at least 67% identical to the homologous peptides from previously published DENV consensus sequences (Fig. 5B). Using Fisher’s test, we found that the proportion of ZIKV epitopes that resulted in a high-magnitude response was significantly different (P = 0.0136) between peptides with $67% sequence identity to DENV and those with ,67% identity (Fig. 5B).
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