Significant control of Zika infection in macaques depends on the elapsing time after dengue exposure

Abstract

29Prior exposure to a single serotype of dengue virus (DENV) predisposes individuals to severe 30 disease upon secondary heterologous DENV infection. Here we show that the length of time 31 between DENV/Zika (ZIKV) infections has a qualitative impact on controlling ZIKV replication. 32We identified limited but significant differences in the magnitude of the early humoral immune 33 response associated with a period of twelve months but not three months of DENV 34 convalescence. However, their role limiting ZIKV replication is not conclusive. There was no 35 evidence of in vivo antibody-dependent amplification of ZIKV by DENV immunity in any group. 36We are also showing that the significant differences among groups may be linked to a pre-37 existing polyfunctional CD4+ T cells response (increased IFN-g and Cd107a before ZIKV 38 infection) and to an early and continuous expansion of the CD4+ effector memory cells early on 39 after ZIKV infection. Those significant differences were associated with a period of 12 months 40 after DENV infection that were not observed in a span of 3-months. These results suggest that 41 there is a window of optimal cross-protection between ZIKV and DENV with significant 42 consequences. These results have pivotal implications while interpreting ZIKV pathogenesis in 43 flavivirus-experimented populations, diagnostic results interpretation and vaccine designs 44 among others. 45 46 Author Summary 47impact on controlling the ZIKV infection. In this study, as in our prior work we did not observe 100 evidence of ZIKV disease enhancement associated with prior DENV exposure. We also 101 confirmed that the significant differences among groups are mediated by the pre-existence of a 102 robust effector memory T cell (TEM) and cytotoxic activity mainly mediated by CD4 + T cells 103 more than qualitative differences in the humoral immune response. However, by conducting a 104 detailed study of the ZIKV-neutralizing titers vs. ZIKV RNAemia at early time points after 105 infection, we were able to determine a possible contribution of the neutralizing antibodies 106 limiting the ZIKV replication at 7 days after infection in the animals with 12 months but not 3 107 months of DENV immunity or in the control group. Overall, we demonstrated that exposure to 108 ZIKV 12 months after DENV infection afford a high level of T cell-mediated cross protection than 109 it was observed at the 3-month span. Based on our previous study we believe this protection 110 wanes as macaques exposed to ZIKV 2.8 years after DENV were not afforded this protection. 111These results suggest that there is a window of optimal T cell cross-protection between ZIKV 112 and DENV. 113 114 Results 115