Abstract
Different strains within a dengue serotype (DENV1-4) can have smooth, or "bumpy" surface morphologies with different antigenic characteristics at average body temperature (37°C). We determined the neutralizing properties of a serotype cross-reactive human monoclonal antibody (HMAb) 1C19 for strains with differing morphologies within the DENV1 and DENV2 serotypes. We mapped the 1C19 epitope to E protein domain II by hydrogen deuterium exchange mass spectrometry, cryoEM and molecular dynamics simulations, revealing that this epitope is likely partially hidden on the virus surface. We showed the antibody has high affinity for binding to recombinant DENV1 E proteins compared to those of DENV2, consistent with its strong neutralizing activities for all DENV1 strains tested regardless of their morphologies. This finding suggests that the antibody could out-compete E-to-E interaction for binding to its epitope. In contrast, for DENV2, HMAb 1C19 can only neutralize when the epitope becomes exposed on the bumpy-surfaced particle. Although HMAb 1C19 is not a suitable therapeutic candidate, this study with HMAb 1C19 shows the importance of choosing a high-affinity antibody that could neutralize diverse dengue virus morphologies for therapeutic purposes.
Highlights
Dengue virus (DENV), a flavivirus, infects about 390 million people each year [1]
Dengue virus consists of four serotypes (DENV1-4) and there are different strains within a serotype
The modeled Class I and II DENV1 strain WestPac 74– Fab 1C19 complex structures were deposited in the Protein Data Bank under accession codes 7DWT and 7DWU, respectively
Summary
Dengue virus (DENV), a flavivirus, infects about 390 million people each year [1]. Infection with one serotype elicits lifelong protection against that particular serotype, in a second infection with another serotype, the antibodies already present inside the patient may not be able to neutralize the second serotype leading to enhancement of disease severity. A safe and effective vaccine will have to incorporate viruses from all serotypes, and the host recipient must elicit high protective immunity against DENV1-4. Development of an effective dengue vaccine has been extremely challenging. Our previous results [11,12] revealed that dengue virus can change its shape (smooth to bumpy surface or clubshape morphology) to escape from the immune system, and spontaneously undergo mutations that influence such shape changes, further complicating development of vaccines that may be prone to emergence of resistance. We study the effect of an antibody against different DENV morphologies
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