BACKGROUND: The gp120 exterior envelope glycoprotein of HIV-1 binds sequentially to CD4 and chemokine receptors on cells to initiate virus entry. During natural infection, gp120 is a primary target of the humoral immune response, and it has evolved to resist antibody-mediated neutralization. We previously reported the structure at 2.5 A of a gp120 core from the HXBc2 laboratory-adapted isolate in complex with a 2 domain fragment of CD4 and the antigen binding fragment of a human antibody. This revealed atomic details of gp120-receptor interactions and suggested multiple mechanisms of immune evasion. RESULTS: We have now extended the HXBc2 structure in P222, crystals to 2.2 A. The enhanced resolution enabled a more accurate modeling of less-well-ordered regions and provided conclusive identification of the density in the central cavity at the crux of the gp120-CD4 interaction as isopropanol from the crystallization medium. We have also determined the structure of a gp120 core from the primary clinical HIV-1 isolate, YU2, in the same ternary complex but in a C2 crystal lattice. Comparisons of HXBc2 and YU2 showed that while CD4 binding was rigid, portions of the gp120 core were conformationally flexible; overall differences were minor, with sequence changes concentrated on a surface expected to be exposed on the envelope oligomer. CONCLUSIONS: Despite dramatic antigenic differences between primary and laboratory-adapted HIV-1, the gp120 cores from these isolates are remarkably similar. Taken together with chimeric substitution and sequence analysis, this indicates that neutralization resistance is specified by quaternary interactions involving the major variable loops and thus affords a mechanism for viral adaptation. Conservation of the central cavity suggests the possibility of therapeutic inhibitors. The structures reported here extend in detail and generality our understanding of the biology of the gp120 envelope glycoprotein.
BACKGROUND: The gp120 exterior envelope glycoprotein of HIV-1 binds sequentially to CD4 and chemokine receptors on cells to initiate virus entry. During natural infection, gp120 is a primary target of the humoral immune response, and it has evolved to resist antibody-mediated neutralization. We previously reported the structure at 2.5 A of a gp120 core from the HXBc2 laboratory-adapted isolate in complex with a 2 domain fragment of CD4 and the antigen binding fragment of a human antibody. This revealed atomic details of gp120-receptor interactions and suggested multiple mechanisms of immune evasion. RESULTS: We have now extended the HXBc2 structure in P222, crystals to 2.2 A. The enhanced resolution enabled a more accurate modeling of less-well-ordered regions and provided conclusive identification of the density in the central cavity at the crux of the gp120-CD4 interaction as isopropanol from the crystallization medium. We have also determined the structure of a gp120 core from the primary clinical HIV-1 isolate, YU2, in the same ternary complex but in a C2 crystal lattice. Comparisons of HXBc2 and YU2 showed that while CD4 binding was rigid, portions of the gp120 core were conformationally flexible; overall differences were minor, with sequence changes concentrated on a surface expected to be exposed on the envelope oligomer. CONCLUSIONS: Despite dramatic antigenic differences between primary and laboratory-adapted HIV-1, the gp120 cores from these isolates are remarkably similar. Taken together with chimeric substitution and sequence analysis, this indicates that neutralization resistance is specified by quaternary interactions involving the major variable loops and thus affords a mechanism for viral adaptation. Conservation of the central cavity suggests the possibility of therapeutic inhibitors. The structures reported here extend in detail and generality our understanding of the biology of the gp120 envelope glycoprotein.
Authors: Shi-Hua Xiang; Peter D Kwong; Rishi Gupta; Carlo D Rizzuto; David J Casper; Richard Wyatt; Liping Wang; Wayne A Hendrickson; Michael L Doyle; Joseph Sodroski Journal: J Virol Date: 2002-10 Impact factor: 5.103
Authors: Rogier W Sanders; Mika Vesanen; Norbert Schuelke; Aditi Master; Linnea Schiffner; Roopa Kalyanaraman; Maciej Paluch; Ben Berkhout; Paul J Maddon; William C Olson; Min Lu; John P Moore Journal: J Virol Date: 2002-09 Impact factor: 5.103
Authors: Aran F Labrijn; Pascal Poignard; Aarti Raja; Michael B Zwick; Karla Delgado; Michael Franti; James Binley; Veronique Vivona; Christoph Grundner; Chih-Chin Huang; Miro Venturi; Christos J Petropoulos; Terri Wrin; Dimiter S Dimitrov; James Robinson; Peter D Kwong; Richard T Wyatt; Joseph Sodroski; Dennis R Burton Journal: J Virol Date: 2003-10 Impact factor: 5.103
Authors: Qi Guo; Hsu-Tso Ho; Ira Dicker; Li Fan; Nannan Zhou; Jacques Friborg; Tao Wang; Brian V McAuliffe; Hwei-Gene Heidi Wang; Ronald E Rose; Hua Fang; Helen T Scarnati; David R Langley; Nicholas A Meanwell; Ralph Abraham; Richard J Colonno; Pin-Fang Lin Journal: J Virol Date: 2003-10 Impact factor: 5.103