NEUTRALIZATION OF DENGUE VIRUS SEROTYPE II BY POTENT HUMAN MONOCLONAL ANTIBODIES

Abstract

DENGUE VIRUS (DENV) INFECTS 400 MILLION PEOPLE ANNUALLY. THERE ARE NO APPROVED VACCINES OR THERAPEUTICS. HERE I HAVE CHARACTERIZED TWO DENV2-SPECIFIC NEUTRALIZING HUMAN MONOCLONAL ANTIBODIES (HMABS). USING X-RAY CRYSTALLOGRAPHY AND CRYO-ELECTRON MICROSCOPY (CRYO-EM), EPITOPES OF HMABS 3F9 AND 10.15 WERE IDENTIFIED TO BE LOCALIZED AT DOMAIN I AND III OF THE ENVELOPE (E) PROTEIN, RESPECTIVELY. THE CRYO-EM STRUCTURE OF FAB 3F9 COMPLEXED WITH DENV2 STRAIN PVP94/07 SHOWED THAT IT BOUND TO 120 COPIES OF THE 180 E PROTEINS ON THE VIRUS SURFACE. HOWEVER, FAB10.15 ONLY RECOGNIZED 60 COPIES OF THEM. INTERESTINGLY, HMAB10.15 IS MORE POTENT AGAINST DENV2 STRAIN NGC AND ITS BINDING RESULTED IN A HIGH PORTION OF BROKEN PARTICLES. IN ADDITION, IGG10.15 WAS MUCH MORE POTENT THAN FAB10.15, LIKELY DUE TO ITS LARGER STERIC HINDRANCE. THESE FINDINGS SHOW THE COMPLEXITY OF ANTIBODY- FLAVIVIRUS INTERACTION AND PROVIDE VALUABLE CLUES IN THE SELECTION OF NEUTRALIZING ANTIBODIES FOR THERAPEUTIC PURPOSES.