Antibody responses to dengue virus protein targets and antibody functions

(Panel A) The dengue virus life cycle and sources of antigens are shown. Dengue virions bind to cell surface receptors (these have not been completely characterized), and the virions are internalized through endocytosis. Acidification of the endocytic vesicle leads to rearrangement of the surface envelope (E) glycoprotein, fusion of the viral and vesicle membranes and release of viral RNA into the cytoplasm. Viral genomic RNA is then translated to produce viral proteins in endoplasmic reticulum (ER)‑derived membrane structures, and the viral proteins and newly synthesized viral RNA assemble into immature virions within the ER lumen. Cleavage of the viral precursor membrane (pre‑M) protein by the host cell enzyme furin leads to the formation of mature virions, which are secreted from the cell. In addition, some of the synthesized non-structural protein 1 (NS1) is expressed on the plasma membrane of the cell or secreted, and some virions are secreted in an immature form. Mature and immature virions induce antibody responses to the E protein, and these antibodies can function in neutralization or in antibody-dependent enhancement of infection. Immature virions also induce antibody responses to the pre‑M protein. Antibodies specific for NS1 can interact with membrane-bound NS1 and cause complement-dependent lysis of virus-infected cells.
(Panel B) The structure of the dengue virus E glycoprotein ectodomain and characteristics of E protein‑specific antibodies are shown. The three domains of the E protein are coloured in red (domain I), yellow (domain II) and blue (domain III).
(Panel C) The mechanisms of neutralization and enhancement by dengue virus-specific antibodies are shown. At high levels of epitope occupancy, antibodies can block the binding of virions to the cellular receptor or can block fusion at a post-binding stage. At lower epitope occupancy levels, antibodies can enhance the uptake of virions into cells by interacting with immunoglobulin (Fc) receptors.