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 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 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.

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)

scholarly journals Sensitivity to a Nonpeptidic Compound (RPR103611) Blocking Human Immunodeficiency Virus Type 1 Env-Mediated Fusion Depends on Sequence and Accessibility of the gp41 Loop Region

2000 ◽  
Vol 74 (5) ◽  
pp. 2142-2150 ◽  
Author(s):  
Béatrice Labrosse ◽  
Carole Treboute ◽  
Marc Alizon
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Conformational Changes ◽  
Loop Region ◽  
Immunodeficiency Virus ◽  
The Stability ◽  
Hiv 1

ABSTRACT The triterpene RPR103611 is an efficient inhibitor of membrane fusion mediated by the envelope proteins (Env, gp120-gp41) of CXCR4-dependent (X4) human immunodeficiency virus type 1 (HIV-1) strains, such as HIV-1LAI (LAI). Other X4 strains, such as HIV-1NDK (NDK), and CCR5-dependent (R5) HIV-1 strains, such as HIV-1ADA (ADA), were totally resistant to RPR103611. Analysis of chimeric LAI-NDK Env proteins identified a fragment of the NDK gp41 ectodomain determining drug resistance. A single difference at position 91, leucine in LAI and histidine in NDK, apparently accounted for their sensitivity or resistance to RPR103611. We had previously identified a mutation of isoleucine 84 to serine in a drug escape LAI variant. Both I84 and L91 are located in the “loop region” of gp41 separating the proximal and distal helix domains. Nonpolar residues in this region therefore appear to be important for the antiviral activity of RPR103611 and are possibly part of its target. However, another mechanism had to be envisaged to explain the drug resistance of ADA, since its gp41 loop region was almost identical to that of LAI. Fusion mediated by chimeric Env consisting of LAI gp120 and ADA gp41, or the reciprocal construct, was fully blocked by RPR103611. The gp120-gp41 complex of R5 strains is stable, relative to that of X4 strains, and this stability could play a role in their drug resistance. Indeed, when the postbinding steps of ADA infection were performed under mildly acidic conditions (pH 6.5 or 6.0), a treatment expected to favor dissociation of gp120, we achieved almost complete neutralization by RPR103611. The drug resistance of NDK was partially overcome by preincubating virus with soluble CD4, a gp120 ligand inducing conformational changes in the Env complex. The antiviral efficacy of RPR103611 therefore depends on the sequence of the gp41 loop and the stability of the gp120-gp41 complex, which could limit the accessibility of this target.

scholarly journals Proteolytic Processing of the Human Immunodeficiency Virus Envelope Glycoprotein Precursor Decreases Conformational Flexibility

2012 ◽  
Vol 87 (3) ◽  
pp. 1884-1889 ◽  
Author(s):  
Hillel Haim ◽  
Ignacio Salas ◽  
Joseph Sodroski
Keyword(s):  
Human Immunodeficiency Virus ◽  
Envelope Glycoprotein ◽  
Conformational Flexibility ◽  
Proteolytic Processing ◽  
Virus Envelope ◽  
Glycoprotein Precursor ◽  
Trimeric Complex ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACTThe mature envelope glycoprotein (Env) spike on the surface of human immunodeficiency virus type 1 (HIV-1) virions is derived by proteolytic cleavage of a trimeric gp160 glycoprotein precursor. Remarkably, proteolytic processing of the HIV-1 Env precursor results in changes in Env antigenicity that resemble those associated with glutaraldehyde fixation. Apparently, proteolytic processing of the HIV-1 Env precursor decreases conformational flexibility of the Env trimeric complex, differentially affecting the integrity/accessibility of epitopes for neutralizing and nonneutralizing antibodies.

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