Globally, the four serotypes of DENV cause an estimated 390 million new cases of dengue fever and 500,000 cases of dengue hemorrhagic fever (DHF) per year. Zika virus (ZIKV) is a related emerging virus linked to Guillain-Barre syndrome in adults, and microcephaly, congenital malformations, and spontaneous abortion of the fetus during pregnancy. Currently, no antiviral therapy is available for either virus. In the first two cycles of this collaborative and inter-disciplinary R01, we developed panels of monoclonal antibodies (Abs) against the E proteins of all four DENV serotypes and analyzed their structural, biophysical, and cellular mechanisms of neutralization. These studies defined novel epitopes on DENV E proteins recognized by inhibitory Abs, some of which are not solvent-accessible according to existing atomic models of the virus particle. We also defined the dynamic state of DENV and related flaviviruses, determined the atomic structure of mature and immature ZIKV, characterized atomic interactions between DENV and ZIKV virions, E protein, and new highly neutralizing mouse and human Abs, and identified how different maturation states influence epitope accessibility and Ab neutralization. Our studies revealed that flavivirus structure is more complex than anticipated and is likely a heterogeneous and dynamic ensemble of different states, each of which may interact differentially with Abs. In this renewal, our collaborative and inter-disciplinary team hopes to gain insight into questions about the antigenicity of flavivirus virions and subviral particles (SVPs) as well as the cross-reactivity that limits vaccine and diagnostic development and may affect pathogenesis. Our group will define new states of DENV and ZIKV particle structure and determine how these states influence epitope exposure and interaction with specific neutralizing Abs available in our laboratories. We also will compare the atomic structure of SVPs with infectious virions, determine how these differences affect binding and induction of neutralization Abs, and characterize further the structural basis of cross-reactivity of DENV and ZIKV. Our studies may facilitate the generation of novel antigens and immunogens with improved capacity to detect and elicit specific protective Ab responses against DENV, ZIKV, and likely other emerging flaviviruses.
The goal of this application is to define new states of DENV and ZIKV particle structure and determine how these impact interaction with specific Abs. Understanding the structural basis of DENV and ZIKV antigenicity will facilitate the development of vaccines that protect against these emerging flaviviruses and diagnostic reagents to monitor serological responses in the context of natural infection or immunization.
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