Abstract
Zika virus (ZIKV) Infection has several outcomes from asymptomatic exposure to rash, conjunctivitis, Guillain-Barré syndrome or congenital Zika syndrome. Analysis of ZIKV immunity is confounded by the fact that several related Flaviviruses infect humans, including Dengue virus 1–4, West Nile virus and Yellow Fever virus. HLA class II restricted T cell cross-reactivity between ZIKV and other Flaviviruses infection(s) or vaccination may contribute to protection or to enhanced immunopathology. We mapped immunodominant, HLA class II restricted, CD4 epitopes from ZIKV Envelope (Env), and Non-structural (NS) NS1, NS3 and NS5 antigens in HLA class II transgenic mice. In several cases, ZIKV primed CD4 cells responded to homologous sequences from other viruses, including DENV1–4, WNV or YFV. However, cross-reactive responses could confer immune deviation - the response to the Env DENV4 p1 epitope in HLA-DR1 resulted in IL-17A immunity, often associated with exacerbated immunopathogenesis. This conservation of recognition across Flaviviruses, may encompass protective and/or pathogenic components and poses challenges to characterization of ZIKV protective immunity.
Highlights
Zika virus (ZIKV) is a Flavivirus, first discovered in 1947 in Uganda and named after the Zika Forest1–3
Using immunization of Human leukocyte antigen (HLA) class II transgenics with ZIKV antigen, and acute infection of AG129 mice, we describe a large array of ZIKV CD4 T cell epitopes, the most comprehensive far
Mapping immunodominant CD4 T cell ZIKV epitopes in HLA class II transgenic mice
Summary
Zika virus (ZIKV) is a Flavivirus, first discovered in 1947 in Uganda and named after the Zika Forest. Knowledge of immunity to other related Flavivruses such as West Nile virus (WNV), Japanese encephalitis virus (JEV) and Dengue virus (DENV), suggests that it may be predicted that components of anti-viral antibody, CD4 or CD8 responses could themselves be highly pathogenic5–8 The pathogenesis of both WNV and JEV infection encompasses T cell mediated pathology. Non-mutually exclusive hypothesis, is that as with antibody dependent enhancement (ADE) between DENV serotypes, prior immunity to related viruses may potentiate a pathogenic response to subsequent ZIKV exposure or vaccination (or that ZIKV immunity will alter responses to subsequent challenges with viruses such as DENV or YFV)4,11 Such considerations make detailed mapping of interactions between the respective anti-viral repertoires a priority. ZIKV primed T cells can in some cases respond to related epitopes from other Flaviviruses This cross-reactive recognition can result in ‘immune deviation’ of the response to an altered cytokine profile of enhanced Interleukin 17 A (IL-17A).
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