The HIV-1 envelope glycoproteins
The HIV-1 envelope glycoproteins
folding, function and vaccin design
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Table of Contents - 6 1 Introduction - 8 2 Env and HIV transmission - 34 2.1 Differential transmission of HIV-1 by distinct subsets of effector dendritic cells - 34 3 Env antigenicity - 52 3.1 The mannose-dependent epitope for neutralizing antibody 2G12 on HIV-1 glycoprotein gp120 - 52 4 Env folding - 76 4.1 Folding and functionality of HIV-1 envelope glycoprotein disulfide bond mutants: discrepancies between ER quality control verdicts and viral fitness requirements - 76 4.2 A stable ß-sheet fold can substitute for a disulfide bond in HIV-1 gp120 - 98 4.3 Local and distal compensatory changes upon evolution of the HIV-1 envelope glycoproteins lacking the N-terminal disulfide bond in gp120 - 118 5 Env modifications for vaccines - 128 5.1 A recombinant HIV-1 envelope glycoprotein complex stabilized by an intermolecular disulfide bond between the gp120 and gp41 subunits is an antigenic mimic of the trimeric virion-associated structure - 128 5.2 Variable loop-deleted variants of the HIV-1 envelope glycoprotein can be stabilized by the introduction of an intermolecular disulfide bridge between the gp120 and gp41 subunits - 162 5.3 Biophysical and antigenic properties of a proteolytically mature, disulfide stabilized HIV-1 gp140 envelope glycoprotein - 182 5.4 Evolution of the HIV-1 envelope glycoproteins with a disulfide bond between gp120 and gp41 - 212 5.5 Enhancing the proteolytic maturation of HIV-1 envelope glycoproteins - 226 5.6 Stabilization of the soluble, trimeric form of the envelope glycoprotein complex of HIV-1 - 248 5.7 Evolutionary repair of HIV-1 gp41 with a kink in the N-terminal helix leads to restoration of the six-helix bundle structure - 276 6 Concluding remarks - 290 Appendix Mutational analyses and natural variability of the gp41 ectodomain - 296 Summary - 322 Samenvatting (Dutch) - 328 Dankwoord (Dutch) - 334 Publications - 336

Rogier Sanders

The HIV-1 envelope glycoproteins

folding, function and vaccin design

The need for a vaccine against HIV is obvious, but the development of an effective vaccine has met with frustrations. The HIV envelope glycoproteins, residing in the viral membrane, are the sole viral proteins exposed on the outside of virus particles and are therefore major targets for vaccine design. The first part of this thesis describes research aimed at understanding the folding and function of the HIV-1 envelope glycoproteins and their properties underlying the effective viral immune evasion. The second part of the thesis describes the design of modifications of the envelope glycoproteins that should improve their properties as vaccine antigens.

Rogier Sanders

Rogier Sanders (1975) studied medical biology at the University of Amsterdam and the Rockefeller University in New York. In 1999 he started his Ph.D. research at the Academic Medical Center of the University of Amsterdam, the results of which are described in this thesis. Rogier performed part of the research at the Aaron Diamond AIDS Research Center (New York), the Scripps Research Institute (San Diego) and Cornell University (New York).