Protective Role of NS1-Specific Antibodies in the Immune Response to Dengue Virus Through Antibody-Dependent Cellular Cytotoxicity

Abstract Background Dengue virus (DENV) nonstructural protein 1 (NS1) has multiple functions within infected cells, on the cell surface, and in secreted form, and is highly immunogenic. Immunity from previous DENV infections is known to exert both positive and negative effects on subsequent DENV infections, but the contribution of NS1-specific antibodies to these effects is incompletely understood. Methods We investigated the functions of NS1-specific antibodies and their significance in DENV infection. We analyzed plasma samples collected in a prospective cohort study prior to symptomatic or subclinical secondary DENV infection. We measured binding to purified recombinant NS1 protein and to NS1-expressing CEM cells, antibody-mediated natural killer (NK) cell activation by plate-bound NS1 protein, and antibody-dependent cellular cytotoxicity (ADCC) of NS1-expressing target cells. Results We found that antibody responses to NS1 were highly serotype cross-reactive and that subjects who experienced subclinical DENV infection had significantly higher antibody responses to NS1 in preinfection plasma than subjects who experienced symptomatic infection. We observed strong positive correlations between antibody binding and NK activation. Conclusions These findings demonstrate the involvement of NS1-specific antibodies in ADCC and provide evidence for a protective effect of NS1-specific antibodies in secondary DENV infection. Antibodies to dengue virus NS1 protein activated NK cells and mediated antibody-dependent cellular cytotoxicity. Higher preexposure antibody responses to NS1 in cohort subjects who experienced subclinical compared to symptomatic dengue virus infections point to a protective role against illness.