(Partly) Unveiling the Mechanism of the Enhanced Immature Dengue Virus Infection by Human prM Antibody

           In response to dengue virus (DENV) infection, the human body generates various antibodies that can recognize the structural proteins (envelope, pre-membrane and capsid) and non-structural proteins (NS1-NS5) of DENV. One type of the antibodies is the anti-prM antibody, which can bind to immature DENV. A significant amount of prM antibodies has been found in the sera of dengue-infected humans. The amount of this type of antibody is substantially higher in patients with secondary infection compared to those with primary infection. These findings indicate the presence of immature DENV particles in DENV-infected human and it may play an important role in the dengue pathogenesis. Interestingly, immature DENV are not supposed to be infectious. This is due to the presence of pr-peptide on the fusion loop, which is located on the tip of the envelope protein. The pr-peptide acts as a cap of the fusion loop, thereby preventing fusion of the virus into the host cell.

          It has been previously shown that prM antibodies facilitate binding and cell entry of immature virus particles into Fc-receptor-expressing cells. In the presence of anti-prM antibodies, immature DENV particles become highly infectious. But, the mechanism behind this was not known. Recently, scientists have revealed the mechanism of how a prM-antibody can enhance the infectivity of immature dengue virus. At neutral pH, antibody 1H10 binds to pr-peptide of the immature dengue virus at high occupancy (180 Fab molecules per particle) as shown by the cryo-EM map of the complex. This virus-antibody complex can bind to Fc-receptor on the host cell through the interactions between the Fc region of the antibody and the Fc-receptor. After endocytosis, the pH inside the endosome decreases to ~pH 5.0. At low pH (pH 5.0), the cryo-EM map of immature DENV: Fab 1H10 complex shows that ~60 pr-Fab molecules are removed from the fusion loop of envelope proteins, leaving these fusion-loop exposed. This exposed fusion-loop may then interact with the host cell membrane and enhance the virus-host cell membranes attachment.