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

1991 ◽  
Vol 174 (2) ◽  
pp. 407-415 ◽  
Author(s):  
Q J Sattentau ◽  
J P Moore
Keyword(s):  
Human Immunodeficiency Virus ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Envelope Glycoprotein ◽  
Fusion Reaction ◽  
Cd4 Cells ◽  
Virus Envelope ◽  
Sequence Of Events ◽  
Immunodeficiency Virus ◽  
Infected Cells

The 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 NH2 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 HIV-infected 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-1-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 degrees C, these conformational changes are coordinate with the dissociation of gp120/sCD4 complexes from gp41, and the increased exposure of gp41 epitopes. At 4 degrees 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 HIV-infected cells and CD4+ cells.

scholarly journals Role of Hydrophobic Residues in the Central Ectodomain of gp41 in Maintaining the Association between Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Subunits gp120 and gp41

2004 ◽  
Vol 78 (9) ◽  
pp. 4921-4926 ◽  
Author(s):  
Joanne York ◽  
Jack H. Nunberg
Keyword(s):  
Human Immunodeficiency Virus ◽  
Conformational Changes ◽  
Envelope Glycoprotein ◽  
Site Directed Mutagenesis ◽  
Amino Acid Residues ◽  
Virus Envelope ◽  
Hydrophobic Residues ◽  
Immunodeficiency Virus ◽  
Mediate Cell ◽  
The Stability

ABSTRACT The interaction between the gp120 and gp41 subunits of the human immunodeficiency virus envelope glycoprotein serves to stabilize the virion form of the complex and to transmit receptor-induced conformational changes in gp120 to trigger the membrane fusion activity of gp41. In this study, we used site-directed mutagenesis to identify amino acid residues in the central ectodomain of gp41 that contribute to the stability of the gp120-gp41 association. We identified alanine mutations at six positions, including four tryptophan residues, which result in mutant envelope glycoprotein complexes that fail to retain gp120 on the cell surface. These envelope glycoproteins readily shed their gp120 and are unable to mediate cell-cell fusion. These findings suggest an important role for the conserved bulky hydrophobic residues in stabilizing the gp120-gp41 complex.

scholarly journals CD4-Induced Conformational Changes in the Human Immunodeficiency Virus Type 1 gp120 Glycoprotein: Consequences for Virus Entry and Neutralization

1998 ◽  
Vol 72 (6) ◽  
pp. 4694-4703 ◽  
Author(s):  
Nancy Sullivan ◽  
Ying Sun ◽  
Quentin Sattentau ◽  
Markus Thali ◽  
Dona Wu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Chemokine Receptor ◽  
Envelope Glycoprotein ◽  
Virus Entry ◽  
Envelope Glycoproteins ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) entry into target cells involves sequential binding of the gp120 exterior envelope glycoprotein to CD4 and to specific chemokine receptors. Soluble CD4 (sCD4) is thought to mimic membrane-anchored CD4, and its binding alters the conformation of the HIV-1 envelope glycoproteins. Two cross-competing monoclonal antibodies, 17b and CG10, that recognize CD4-inducible gp120 epitopes and that block gp120-chemokine receptor binding were used to investigate the nature and functional significance of gp120 conformational changes initiated by CD4 binding. Envelope glycoproteins derived from both T-cell line-adapted and primary HIV-1 isolates exhibited increased binding of the 17b antibody in the presence of sCD4. CD4-induced exposure of the 17b epitope on the oligomeric envelope glycoprotein complex occurred over a wide range of temperatures and involved movement of the gp120 V1/V2 variable loops. Amino acid changes that reduced the efficiency of 17b epitope exposure following CD4 binding invariably compromised the ability of the HIV-1 envelope glycoproteins to form syncytia or to support virus entry. Comparison of the CD4 dependence and neutralization efficiencies of the 17b and CG10 antibodies suggested that the epitopes for these antibodies are minimally accessible following attachment of gp120 to cell surface CD4. These results underscore the functional importance of these CD4-induced changes in gp120 conformation and illustrate viral strategies for sequestering chemokine receptor-binding regions from the humoral immune response.

scholarly journals Localized Changes in the gp120 Envelope Glycoprotein Confer Resistance to Human Immunodeficiency Virus Entry Inhibitors BMS-806 and #155

2004 ◽  
Vol 78 (7) ◽  
pp. 3742-3752 ◽  
Author(s):  
Navid Madani ◽  
Ana Luisa Perdigoto ◽  
Kumar Srinivasan ◽  
Jason M. Cox ◽  
Jason J. Chruma ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Envelope Glycoprotein ◽  
Cell Receptor ◽  
Amino Acid Residues ◽  
Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Entry ◽  
Virus Entry Inhibitors ◽  
Hiv 1

ABSTRACT BMS-806 and the related compound, #155, are novel inhibitors of human immunodeficiency virus type 1 (HIV-1) entry that bind the gp120 exterior envelope glycoprotein. BMS-806 and #155 block conformational changes in the HIV-1 envelope glycoproteins that are induced by binding to the host cell receptor, CD4. We tested a panel of HIV-1 envelope glycoprotein mutants and identified several that were resistant to the antiviral effects of BMS-806 and #155. In the CD4-bound conformation of gp120, the amino acid residues implicated in BMS-806 and #155 resistance line the “phenylalanine 43 cavity” and a water-filled channel that extends from this cavity to the inner domain. Structural considerations suggest a model in which BMS-806 and #155 bind gp120 prior to receptor binding and, upon CD4 binding, are accommodated in the Phe-43 cavity and adjacent channel. The integrity of the nearby V1/V2 variable loops and N-linked carbohydrates on the V1/V2 stem indirectly influences sensitivity to the drugs. A putative binding site for BMS-806 and #155 between the gp120 receptor-binding regions and the inner domain, which is thought to interact with the gp41 transmembrane envelope glycoprotein, helps to explain the mode of action of these drugs.

scholarly journals A V3 Loop-Dependent gp120 Element Disrupted by CD4 Binding Stabilizes the Human Immunodeficiency Virus Envelope Glycoprotein Trimer

2010 ◽  
Vol 84 (7) ◽  
pp. 3147-3161 ◽  
Author(s):  
Shi-Hua Xiang ◽  
Andrés Finzi ◽  
Beatriz Pacheco ◽  
Kevin Alexander ◽  
Wen Yuan ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Receptor Binding ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Envelope Glycoproteins ◽  
V3 Loop ◽  
Virus Envelope ◽  
Hydrophobic Patch ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus (HIV-1) entry into cells is mediated by a trimeric complex consisting of noncovalently associated gp120 (exterior) and gp41 (transmembrane) envelope glycoproteins. The binding of gp120 to receptors on the target cell alters the gp120-gp41 relationship and activates the membrane-fusing capacity of gp41. Interaction of gp120 with the primary receptor, CD4, results in the exposure of the gp120 third variable (V3) loop, which contributes to binding the CCR5 or CXCR4 chemokine receptors. We show here that insertions in the V3 stem or polar substitutions in a conserved hydrophobic patch near the V3 tip result in decreased gp120-gp41 association (in the unliganded state) and decreased chemokine receptor binding (in the CD4-bound state). Subunit association and syncytium-forming ability of the envelope glycoproteins from primary HIV-1 isolates were disrupted more by V3 changes than those of laboratory-adapted HIV-1 envelope glycoproteins. Changes in the gp120 β2, β19, β20, and β21 strands, which evidence suggests are proximal to the V3 loop in unliganded gp120, also resulted in decreased gp120-gp41 association. Thus, a gp120 element composed of the V3 loop and adjacent beta strands contributes to quaternary interactions that stabilize the unliganded trimer. CD4 binding dismantles this element, altering the gp120-gp41 relationship and rendering the hydrophobic patch in the V3 tip available for chemokine receptor binding.

Human immunodeficiency virus envelope glycoprotein 120 alters sleep and induces cytokine mRNA expression in rats

1996 ◽  
Vol 271 (2) ◽  
pp. 1-1 ◽  
Author(s):  
M. R. Opp ◽  
P. L. Rady ◽  
T. K. Hughes ◽  
P. Cadet ◽  
S. K. Tyring ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mrna Expression ◽  
Envelope Glycoprotein ◽  
Cytokine Mrna ◽  
Virus Envelope ◽  
Cytokine Mrna Expression ◽  
Human Immunodeficiency Virus Envelope ◽  
Immunodeficiency Virus

Pages R963–R970: M. R. Opp, P. L. Rady, T. K. Hughes, Jr., P. Cadet, S. K. Tyring, and E. M. Smith. “Human immunodeficiency virus envelope glycoprotein 120 alters sleep and induces cytokine mRNA expression in rats.” On p. R968, Fig. 3 should appear as below. (See PDF)

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