Our main objective was to define viral antigens and epitopes recognized by 2 individuals exposed to primary DENV infections. In both these subjects the dengue virion was a major target of the humoral immune response but many of these antibodies did not bind to rE protein. The DENV virion displays 180 E and 180 prM or M proteins that are arrayed with pseudo-icosahedral symmetry. Depending on the maturation state of the virus particle, the 180 E protein molecules are organized as 90 head-to-tail dimers that lie flat on the virion surface or 60 trimers that protrude as spikes from the surface [35] . Since the E protein, with ,500 amino acids, is considerably larger than the 166 amino acid prM protein, the majority of surface exposed viral protein consists of the ectodomain of E. Thus, our finding that many antibodies bound to epitopes on the virus that were not preserved on rE was somewhat unexpected. These findings are consistent with the results of another study from our group [30] as well as a study by Dejnirattisai and colleagues who observed that many hMAbs that bound to DENV particles did not bind to rE protein [25] . As the rE protein used in the current study lacked ,20% of the protein, which include the membrane proximal regions and the transmembrane domains, it is possible that some antibodies bind to these regions. Moreover, antibodies may recognize E protein epitopes that are only available in the context of the native oligomeric array on the virion. Several hMAbs generated from individuals infected with West Nile virus bound the virion but not rE protein; these hMAbs recognized epitopes that were created by adjacent E protein molecules on the surface of the virion or formed by hinge regions [36] .