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.
Author(s): Rogier W. Sanders
Year: 2004
Language: English
Pages: 338
Table of Contents......Page 6
1 Introduction......Page 8
2.1 Differential transmission of HIV-1 by distinct subsets of effector dendritic cells......Page 34
3.1 The mannose-dependent epitope for neutralizing antibody 2G12 on HIV-1 glycoprotein gp120......Page 52
4.1 Folding and functionality of HIV-1 envelope glycoprotein disulfide bond mutants: discrepancies between ER quality control verdicts and viral fitness requirements......Page 76
4.2 A stable β-sheet fold can substitute for a disulfide bond in HIV-1 gp120......Page 98
4.3 Local and distal compensatory changes upon evolution of the HIV-1 envelope glycoproteins lacking the N-terminal disulfide bond in gp120......Page 118
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......Page 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......Page 162
5.3 Biophysical and antigenic properties of a proteolytically mature, disulfide stabilized HIV-1 gp140 envelope glycoprotein......Page 182
5.4 Evolution of the HIV-1 envelope glycoproteins with a disulfide bond between gp120 and gp41......Page 212
5.5 Enhancing the proteolytic maturation of HIV-1 envelope glycoproteins......Page 226
5.6 Stabilization of the soluble, trimeric form of the envelope glycoprotein complex of HIV-1......Page 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......Page 276
6 Concluding remarks......Page 290
Appendix Mutational analyses and natural variability of the gp41 ectodomain......Page 296
Summary......Page 322
Samenvatting (Dutch)......Page 328
Dankwoord (Dutch)......Page 334
Publications......Page 336
