Viral Load and Cytokine Response Profile Does Not Support Antibody-Dependent Enhancement in Dengue-Primed Zika Virus-Infected Patients

Abstract

Background: The pathogenesis of severe dengue disease involves immune components as biomarkers. The mechanism by which some dengue virus (DENV)-infected individuals progress to severe disease is poorly understood. Most studies on the pathogenesis of severe dengue disease focus on the process of antibody-dependent enhancement (ADE) as a primary risk factor. With the circulation of Zika virus (ZIKV) in DENV-endemic areas, many people infected by ZIKV were likely exposed to DENV. The influence of such exposure on Zika disease outcomes remains unknown.

Methods: We investigated whether patients previously exposed to DENV exhibited higher viremia when exposed to a subsequent, heterologous dengue or Zika infection than those patients not previously exposed to dengue. We measured viral loads and cytokine profile during patients' acute infections.

Results: Neither dengue nor Zika viremia was higher in patients with prior DENV infection, although the power to detect such a difference was only adequate in the ZIKV analysis. Of the 10 cytokines measured, only 1 significant difference was detected: Levels of interleukin 1β (IL-1β) were lower in dengue-infected patients who had experienced a previous dengue infection than patients infected with dengue for the first time. However, power to detect differences between groups was low. In Zika-infected patients, levels of IL-1β showed a significant, positive correlation with viral load.

Conclusions: No signs of ADE were observed in vivo in patients with acute ZIKV infection who had prior exposure to DENV.

Keywords: ADE; DENV; ZIKV; cytokines.

Figure 1.

Viral load in patients with Zika virus (ZIKV) and dengue virus (DENV) serotype 2 during primary and secondary dengue infections. A, Viral load quantified in ZIKV-positive patients with primary (immunoglobulin G–negative [IgG^–]) DENV infection (n = 10) and secondary (immunoglobulin G–positive [IgG⁺]) DENV infection (n = 35). The Mann-Whitney U test demonstrated no significant difference in viral load. B, Viral load quantified in DENV 2⁺ patients with primary (IgG^–) DENV infection (n = 6) and secondary (IgG⁺) DENV infection (n = 14). The Mann-Whitney U test demonstrated no significant difference in viral load. Medians with interquartile range are shown.

Figure 2.

Cytokine (interleukin [IL]; interferon [IFN]) response in patients with dengue virus (DENV) serotype 2 and Zika virus (ZIKV) during primary and secondary dengue infections. A, Cytokine levels measured in DENV 2-positive patients with primary (immunoglobulin G–negative [IgG^–]) DENV infection (n = 06) and secondary (immunoglobulin G–positive [IgG⁺]) DENV infection (n = 14). The Mann-Whitney U test demonstrated a significant P value in the cases of IL-1β (*P = .0039), IL-6 (**P = .0133), IL-8 (***P = .0477), and IL-9 (****P = .0391). B, Cytokine levels measured in ZIKV-positive patients with primary (IgG^–) DENV infection (n = 10) and secondary (IgG⁺) DENV infection (n = 35). The Mann-Whitney U test demonstrated no significant P value.