The crown and stem of the V3 loop play distinct roles in human immunodeficiency virus type 1 envelope glycoprotein interactions with the CCR5 coreceptor - PubMed (original) (raw)
The crown and stem of the V3 loop play distinct roles in human immunodeficiency virus type 1 envelope glycoprotein interactions with the CCR5 coreceptor
Emmanuel G Cormier et al. J Virol. 2002 Sep.
Abstract
Human immunodeficiency virus type 1 envelope glycoprotein gp120 interacts with CD4 and the CCR5 coreceptor in order to mediate viral entry. A CD4-induced surface on gp120, primarily composed of residues in the V3 loop and the C4 domain, interacts with CCR5. In the present study, we generated envelope glycoproteins comprising chimeric V3 loops and/or V3 loops with deletions and studied their binding to CCR5 amino-terminal domain (Nt)-based sulfopeptides and cell surface CCR5, as well as their ability to mediate viral entry. We thus delineated two functionally distinct domains of the V3 loop, the V3 stem and the V3 crown. The V3 stem alone mediates soluble gp120 binding to the CCR5 Nt. In contrast, both the V3 stem and crown are required for soluble gp120 binding to cell surface CCR5. Within the context of a virion, however, the V3 crown alone determines coreceptor usage. Our data support a two-site gp120-CCR5 binding model wherein the V3 crown and stem interact with distinct regions of CCR5 in order to mediate viral entry.
Figures
FIG. 1.
Sequence comparisons of the JR-FL and LAI V3 loops. The amino acid sequences of the JR-FL and LAI V3 loops were aligned, and identical residues are indicated by vertical lines between the two sequences. Residues are numbered according to the gp120HxB2 sequence. Residues within the crowns of the V3 loops are in boldface.
FIG. 2.
gp120 chimera and deletion mutant binding to the CCR5 Nt sulfopeptide. The CCR5 Nt sulfopeptide comprising residues 2 to 18 was immobilized on streptavidin-coated plates and incubated with soluble gp120-CD4 complexes. The gp120 chimera and deletion mutants are on the x axis. Mutant gp120JR-FL-CD4-IgG2 binding to the sulfopeptide is expressed as a percentage of wild-type gp120JR-FL-CD4-IgG2 binding. The values shown are averages of three independent experiments.
FIG. 3.
gp120 chimera and deletion mutant binding to CCR5+ cells. L12 CCR5+ cells (106) were incubated with soluble gp120-CD4 complexes (20 nM gp120 and 5 nM CD4-IgG2) in the absence (white bars) or presence (gray bars) of MAb PA14 (10 μg/ml), and binding was detected by flow cytometry analysis. The gp120 chimeras and deletion mutants are indicated along the x axis. Mutant gp120JR-FL-CD4-IgG2 binding to the cells is expressed as a percentage of wild-type JR-FL-CD4-IgG2 binding. The values shown are averages of three independent experiments.
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