Antibody-antigen interactions in Dengue virus

Individuals that survive a viral infection have antibodies (Abs) capable of detecting and neutralizing subsequent attacks by the same virus. These Abs bind antigens (Ags), often viral proteins, through specific atomic interactions between the Ab and the region of the Ag that it recognizes (epitope). A better understanding of these interactions is expected to accelerate vaccine development, since most current vaccines are based on the generation of neutralizing Ab responses.
If we understand the structural rules governing Ab-Ag interactions in a given virus, then we have the molecular basis to attempt to design and synthesize new epitopes to be used as vaccines or optimize the antibodies themselves for passive immunization. Comparing the binding of several different antibodies to related Ags should also further our understanding of general principles of recognition.
We recently proposed an experimentally validated computational approach for the rapid, systematic characterization of Ab-Ag complexes. Schematically, we isolate Abs from the blood of human donors infected with a given virus; produce and purify milligram quantities of human monoclonal antibodies; characterize their immunological and biophysical properties; determine their epitope through NMR epitope mapping; use the NMR results to drive and validate computational docking simulations to obtain the structure of their complex with the desired antigen.

Here we propose to apply this approach to Dengue Virus (DENV), a neglected disease causing 500,000 hospitalizations and 20,000 deaths per year. No cure or vaccine for DENV is currently available. The effort to find one has been hampered by the presence of four different serotypes and by a poorly understood process, Antibody-Dependent Enhancement, where antibodies raised against a previous Dengue infection facilitate subsequent infection by a different serotype.

Our aim is to compare a large number of antibodies bound to the surface protein of the four Dengue serotypes, searching for correlations between immunological and structural trends and exploiting them to further our understanding of antibody/antigen interaction, as well as a basis for drug design and improved vaccine strategies. In a simplistic example, should we find that all Abs effective against DENV4 have a positive charge in a particular three-dimensional position, we would try to introduce such a charge in Abs lacking it, thus improving their characteristics. Conversely, should all effective Abs against a certain serotype recognize a particular epitope, then it would be conceivable to prepare an antigen sharing the best epitopes of each serotype as a possible vaccination agent.