Abstract
Dengue viruses (DENV) are mosquito-borne flaviviruses of global importance. DENV exist as four serotypes, DENV1-DENV4. Following a primary infection, individuals produce DENV-specific antibodies that bind only to the serotype of infection and other antibodies that cross-react with two or more serotypes. People exposed to a secondary DENV infection with another serotype are at greater risk of developing more severe forms of dengue disease. The increased risk of severe dengue in people experiencing repeat DENV infections appear to be due, at least in part, to the ability of pre-existing serotype cross-reactive antibodies to form virus-antibody complexes that can productively infect Fcγ receptor-bearing target cells. While the theory of antibody-dependent enhancement (ADE) is supported by several human and small animal model studies, the specific viral antigens and epitopes recognized by enhancing human antibodies after natural infections have not been fully defined. We used antibody-depletion techniques to remove DENV-specific antibody sub-populations from primary DENV-immune human sera. The effects of removing specific antibody populations on ADE were tested both in vitro using K562 cells and in vivo using the AG129 mouse model. Removal of serotype cross-reactive antibodies ablated enhancement of heterotypic virus infection in vitro and antibody-enhanced mortality in vivo. Further depletion studies using recombinant viral antigens showed that although the removal of DENV E-specific antibodies using recombinant E (rE) protein resulted in a partial reduction in DENV enhancement, there was a significant residual enhancement remaining. Competition ADE studies using prM-specific Fab fragments in human immune sera showed that both rE-specific and prM-specific antibodies in primary DENV-immune sera significantly contribute to enhancement of heterotypic DENV infection in vitro. Identification of the targets of DENV-enhancing antibodies should contribute to the development of safe, non-enhancing vaccines against dengue.
Highlights
Dengue is present in over 100 countries and is the most common arthropod-borne viral disease of humans [1,2]
Dengue disease is caused by dengue virus (DENV), which exists as four closely-related serotypes (DENV1-DENV4)
We found that antibodies binding both the envelope and prM proteins on the DENV virion play an important role in antibody-dependent enhancement (ADE) of DENV by human immune sera
Summary
Dengue is present in over 100 countries and is the most common arthropod-borne viral disease of humans [1,2]. Recent studies estimate that approximately 390 million individuals are infected with DENV globally each year, causing around 100 million clinically apparent cases [3]. Primary DENV infections in humans result in type-specific as well as serotype cross-reactive antibodies. During a secondary infection with another DENV serotype, individuals are at a greater risk of severe disease than during a primary infection [4,5,6]. One of the most compelling explanations for the higher proportions of severe disease in infants and secondary heterotypic DENV infections is the phenomenon of antibody-dependent enhancement (ADE) [4,5,6]. ADE of DENV infection is expected to occur when pre-existing sub-neutralizing antibodies (e.g., from a primary infection) bind to a heterotypic virus during a subsequent infection and facilitate the entry of the virus through Fcc receptor
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