Structural Influence on the Dominance of Virus-Specific CD4 T Cell Epitopes in Zika Virus Infection

Abstract

Zika virus (ZIKV) has recently caused explosive outbreaks in Pacific islands, South- and Central America. Like with other flaviviruses, protective immunity is strongly dependent on potently neutralizing antibodies (Abs) directed against the viral envelope protein E. Such Ab formation is promoted by CD4 T cells through direct interaction with B cells that present epitopes derived from E or other structural proteins of the virus. Here, we examined the extent and epitope dominance of CD4 T cell responses to capsid (C) and envelope proteins in Zika patients. All patients developed ZIKV-specific CD4 T cell responses, with substantial contributions of C and E. In both proteins, immunodominant epitopes clustered at sites that are structurally conserved among flaviviruses but have highly variable sequences, suggesting a strong impact of protein structural features on immunodominant CD4 T cell responses. Our data are particularly relevant for designing flavivirus vaccines and their evaluation in T cell assays and provide insights into the importance of viral protein structure for epitope selection and antigenicity.

Cutting Edge: Transcriptional Profiling Reveals Multifunctional and Cytotoxic Antiviral Responses of Zika Virus–Specific CD8+ T Cells

“…Future studies will address the immune profiles of human ZIKV-specific CD4 + T cells and compare the functionalities of CD4 + T cells with the ones of CD8 + T cells. Indeed, recent studies in humans and mouse models have shown the importance of ZIKV-specific CD4 + T cells in protecting from severe ZIKV severe and Ab development (25)(26)(27). Additionally, it would be of interest to test whether disease severity during the acute phase impacts the gene transcription and protein expression in ZIKVspecific T cells.…”

Strong CD4 T Cell Responses to Zika Virus Antigens in a Cohort of Dengue Virus Immune Mothers of Congenital Zika Virus Syndrome Infants

“…While many attempts to examine CD4 T cells responses in ZIKV-exposed donors have relied on screening large peptide pools, we here adopted the strategy of analyzing responses to individual recombinant protein antigens, and individual peptides. Koblischke and colleagues previously mapped responses to a C/PrM/E peptide pool using PBMC from 14 ZIKV + travelers returning to Europe following recovery from acute infection (21). This showed a diverse spread of epitope recognition, with some degree of focused recognition in the region of C protein amino acids 77-107.…”

Impact of flavivirus vaccine-induced immunity on primary Zika virus antibody response in humans

“…TBE and YF NTs were performed as described previously [26,36,37]. Briefly, serial dilutions of serum samples were mixed with TBE virus strain Neudoerfl [38,39] or YF virus strain 17D [40].…”