Conformational changes induced in the human immunodeficiency virus envelope glycoprotein by soluble CD4 binding.

Abstract

SummaryThe human immunodeficiency virus (, HIV) binds to the surface of T lymphocytes and other cells of the immune system via a high affinity interaction between CD4 and the HIV outer envelope glycoprotein, gp120. By analogy with certain other enveloped viruses, receptor binding by HIV may be followed by exposure of the hydrophobic NHZ terminus of its transmembrane glycoprotein, gp41, and fusion of the virus and cell membranes. A similar sequence of events is thought to take place between HIVinfected and uninfected CD4' cells, resulting in their fusion to form syncytia . In this study, we have used a soluble, recombinant form of CD4 (sCD4) to model events taking place after receptor binding by the HIV envelope glycoproteins. We demonstrate that the complexing of sCD4 with gp120 induces conformational changes within envelope glycoprotein oligomers. This was measured on HIV'-infected cells by the increased binding of antibodies to the gp120/V3 loops, and on the surface of virions by increased cleavage of this loop by an exogenous proteinase. At 37°C, these conformational changes are coordinate with the dissociation of gp120ACD4 complexes from gp41, and the increased exposure of gp41 epitopes . At 4°C, gp120 dissociation from the cell surface does not occur, but increased exposure of both gp120/V3 and gp41 epitopes is detected. We propose that these events occurring after CD4 binding are integral components of the membrane fusion reaction between HIV or HIVinfected cells and CD4+ cells.

Nef Stimulates Human Immunodeficiency Virus Type 1 Replication in Primary T Cells by Enhancing Virion-Associated gp120 Levels: Coreceptor-Dependent Requirement for Nef in Viral Replication

“…The differential loss of gp120 between X4-and R5-tropic HIV-1 may be due to differences in the inherent stability of the gp120-gp41 complex, or to differences in gp120 conformational changes induced upon CD4 binding. Previous studies have shown that laboratoryadapted strains of HIV-1, which are generally X4-tropic, readily shed gp120 upon addition of soluble CD4 and are more sensitive to inhibition by sCD4 (31,36,50,61). The preferential inhibition of X4-tropic HIV-1 by sCD4 is also in general agreement with the hypothesis that cellular CD4 is more detrimental for replication of X4-tropic HIV-1.…”

Quaternary structures of HIV Env immunogen exhibit conformational vicissitudes and interface diminution elicited by ligand binding

“…1 C and F) observed between the unliganded and the liganded states can be properly described as a density shift away from the threefold axis in our gp140 structure, but with a constrained extension of the outer domain at the tip of each trimeric blade to the central axis. Whereas the observed density shift of approximately 15 Å correlates well with the tertiary structural change previously measured by the displacement of the V2 loop stem, strands β2 and β3, elicited in the liganded state (7), such density weakening at the junction of gp120 subunits to the gp41 density at the threefold axis may not only sterically facilitate the formation of the gp41 prehairpin intermediate to expose the fusion peptide, but may also contribute to gp120 shedding as previously reported (21,22). As part of the quaternary density movement in the gp140 trimer, the reported tertiary conformational change of gp120 could be operating in concert within the trimer to expose and elicit the conformational change of gp41.…”

Triazine Dyes Inhibit HIV‐1 Entry by Binding to Envelope Glycoproteins

“…Dynamic and sequential interactions occur between viral and cellular proteins after the binding of gp120 to the CD4 receptor. Soluble CD4 enhanced gp120 shedding from infected cell surfaces (1,12), while on the other hand, anti-V3 monoclonal antibodies bound more efficiently to soluble CD4-treated cells (21). The above findings indicate the conformational changes of gp120 after its binding to the CD4 molecule.…”