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Title: Structural analysis of an HIV-neutralizing protein and its complex with native viral gp120 : implications for antiviral drug design
Author: Bennett, A. E.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2008
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I present a three-dimensional structural analysis of (1) the simian immunodeficiency virus (SIV) gp120-gp41 envelope glycoprotein complex, (2) D1D2-Igαtp, a CD4-antibody construct with extreme HIV-neutralizing capability, and (3) the complex of D1D2-Igαtp with native SIV gp120, using cryo electron tomography and atomic force microscopy, in order to better understand structural determinants of HIV neutralization using this model system. Cryo electron tomographic density maps and atomic force micrographs of D1D2-Igαtp show that the 3-9 antibody-like units of this high-molecular-weight polymer appear to be more flexible than the 5-6 antibody arms of IgM, a naturally-occurring polymeric antibody that was analyzed in parallel. When imaged by cryo electron tomography in complex with the gp120-gp41 spikes of frozen-hydrated SIV virions, D1D2-Igαtp molecules were observed to bridge spikes within and between virions. Notably, these complexes were associated with an increased proportion of ruptured virions compared to control experiments. Further, inter-virus spike crosslinking was associated with close apposition of the membranes of the crosslinked virions, effectively neutralizing all spikes on the closely apposed surfaces by preventing access to the target cell surface. These effects suggest that the ratio of neutralized to CD4-liganded gp120 spikes can be much greater than unity, and imply that the potency of D1D2-Igαtp may be due to its flexibility more than to its polyvalence or steric bulk per se. These observations suggest polyvalence presented on a flexible scaffold as a key design criterion for small molecule and low-molecular-weight HIV entry inhibitor drugs.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available