Speaker
Dr
Gavin Owen
(HIV Pathogenesis Research Unit, Department of Molecular Medicine and Haematology, University of the Witwatersrand)
Description
The HPRU has focused on the development of an effective prophylactic HIV vaccine which utilizes a novel immunogen called gp120-2dCD4S60C that consists of a human two domain CD4 with a S60C mutation covalently bound to monomeric gp120. This covalent complex acts as a “super immunogen” in pre-clinical studies in rabbits, where it elicits potent and broadly protective neutralizing antibody responses against HIV-1 Tiers 1, 2, 3, HIV-2 and SIV pseudoviruses. Prior to initiating further preclinical development of the gp120-2dCD4S60C vaccine immunogen in rhesus macaques, it would be critical to characterize and define the structure of the immunogenic HIV-1 gp120-2dCD4S60C complex, and ultimately fine map the specificities of the potent, broadly neutralizing antibodies elicited by the gp120-2dCD4S60C complex in rabbits. The broad aim of this study is therefore to characterize the structure of gp120-2dCD4S60C as compared to gp120 bound to 2dCD4WT. Resolving the architecture of the immunogenic gp120-CD4S60C complex will ultimately be important for defining the structures of the exposed target epitopes of potent neutralizing antibody responses, as compared to those of native non-covalent complex formed with wild-type CD4. Both low-resolution (small-angle x-ray/neutron scattering – SAXS/SANS) and high-resolution (synchrotron X-ray crystallography) structural information will be obtained in collaboration with the Institut Laue-Langevin and European Synchrotron Radiation Facility (ILL-ESRF), both based in Grenoble, France. Only preliminary data has been gained thus far, but it will ultimately assist in gaining insights into the underlying mechanisms of the antiviral activity that will guide strategies for optimizing CD4-based immunogens that will likely provide protection from infection.
Primary author
Dr
Gavin Owen
(HIV Pathogenesis Research Unit, Department of Molecular Medicine and Haematology, University of the Witwatersrand)
Co-authors
Prof.
Maria Papathanasopoulos
(University of the Witwatersrand)
Dr
Mark Killick
(HIV Pathogenesis Research Unit, Department of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Science, University of the Witwatersrand)
Dr
Michael Haertlein
(Institut Laue-Langevin, Partnership for Structural Biology)
Dr
Nichole Cerutti
(HIV Pathogenesis Research Unit, Department of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Science, University of the Witwatersrand)
Prof.
Trevor Forsyth
(Keele University)
Prof.
edward mitchell
(ESRF)
