Immunological evidence for interactions between the first, second, and fifth conserved domains of the gp120 surface glycoprotein of human immunodeficiency virus type 1

Moore, John P.; Willey, R L; Lewis, George K.; Robinson, J.; Sodroski, Joseph

doi:10.1128/jvi.68.11.6836-6847.1994

Cited by 83 publications

(49 citation statements)

References 41 publications

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“…This means that the mutations clustered in the V3 loop do not suffice but that, instead, the whole set of amino acid changes scattered over the whole gp120 molecule seems to be necessary to confer reduced sensitivity to bicyclam derivatives. This points to the importance of the three-dimensional structure of gp120 and also supports the reported interactions between several domains of gp120 (9,11,18). Apparently, the changes brought about by the detected amino acid mutations alter the conformation of gp120 in such a way that gp120 at least partially escapes the inhibitory actions of the bicyclams.…”

Section: Discussionsupporting

confidence: 80%

“…This phenomenon is known for protease inhibitors (15), and reports from Willey et al (17) have indicated that a glycosylation site-deleting substitution in the C2 domain, which reduces HIV infectivity, could be functionally compensated for by a reversion substitution in the C1 domain. Moore and colleagues (11) explored the topologies of the gp120 glycoproteins of the mutant and revertant and found that the C2 substitution disrupted the CD4 binding site, which was restored to its wild-type function by the C1 compensatory substitution. Furthermore, the C2 change caused an abnormal exposure of a large segment of the C1 domain, and the segment was restored to its wild-type conformation by the reversion substitution in C1 (11).…”

Section: Discussionmentioning

confidence: 99%

“…Moore and colleagues (11) explored the topologies of the gp120 glycoproteins of the mutant and revertant and found that the C2 substitution disrupted the CD4 binding site, which was restored to its wild-type function by the C1 compensatory substitution. Furthermore, the C2 change caused an abnormal exposure of a large segment of the C1 domain, and the segment was restored to its wild-type conformation by the reversion substitution in C1 (11). Likewise, some of the mutations observed in the bicyclam-resistant strains may not be involved in an interaction with gp120 but might simply be required to compensate for other amino acid changes that by themselves would disrupt the conformation necessary for productive infection.…”

Section: Discussionmentioning

confidence: 99%

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Sensitivity of human immunodeficiency virus to bicyclam derivatives is influenced by the three-dimensional structure of gp120

Vreese

Nerum

Vermeire

et al. 1997

Antimicrob Agents Chemother

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The bicyclams are a new class of anti-human immunodeficiency virus (anti-HIV) compounds targeted at viral entry. From marker rescue experiments, it appears that the envelope gp120 glycoprotein plays an important role in the anti-HIV activity of the bicyclams. Bicyclam-resistant strains contain a number of amino acid changes scattered over the V2 to V5 region of gp120. Experiments aimed at estimating the relative importance of particular amino acid changes with regard to the overall resistance pattern are described. The sequences of some partially bicyclam-resistant virus strains, obtained during the resistance development process, were analyzed, and the corresponding 50% effective concentrations were determined. Selected mutations observed in bicyclam-resistant strains were introduced in the wild-type background by site-directed mutagenesis. In addition, some amino acids were back-mutated to their wild-type counterparts in an otherwise JM3100-resistant strain. The sensitivities of these mutant viruses to bicyclams were determined. Construction of chimeric viruses, carrying the V3 loop of JM3100-resistant virus in a wild-type HIV type 1 HXB2 background, enabled us to investigate the importance of the mutations in the V3 loop of JM3100-resistant virus. From the results described in the report, it can be concluded that single amino acid substitutions do not influence the observed resistance to JM3100. Also, the mutations in the V3 loop are not sufficient to engender even a partially resistant phenotype. We postulate that the overall conformation of gp120 determines the degree of sensitivity or resistance of HIV strains to bicyclams.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Sensitivity of human immunodeficiency virus to bicyclam derivatives is influenced by the three-dimensional structure of gp120

Vreese

Nerum

Vermeire

et al. 1997

Antimicrob Agents Chemother

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“…The results presented in this report draw us to the conclu-sion that neutralization escape of HIV-1 from natural human sera occurs through single amino acid substitutions that affect the binding of neutralizing antibodies at multiple sites on gp120. Numerous studies have illustrated interactions between envelope regions and how changes in one region can produce alterations in noncontiguous regions (5,18,24,26,27,42,51,53). Thus, our conclusion is not unexpected.…”

Section: Discussionsupporting

confidence: 61%

Resistance of human immunodeficiency virus type 1 to neutralization by natural antisera occurs through single amino acid substitutions that cause changes in antibody binding at multiple sites

Watkins

Buge

Aldrich

et al. 1996

J Virol

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The ability of human immunodeficiency virus type 1 (HIV-1) to replicate in the presence of strong immune responses to the virus may be due to its high mutation rate, which provides envelope gene variability for selection of neutralization-resistant variants. Understanding neutralization escape mechanisms is therefore important for the design of HIV-1 vaccines and our understanding of the disease process. In this report, we analyze mutations at amino acid positions 281 and 582 in the HIV-1 envelope, where substitutions confer resistance to broadly reactive neutralizing antisera from seropositive individuals. Neither of these mutations lies within an antibody-binding site, and therefore the mechanism of immune escape in both cases is by alteration of the shape of the envelope proteins. The conformation of the CD4-binding site is shown to be critical with regard to presentation of other discontinuous epitopes. From our analysis of the neutralization of these variants, we conclude that escape from polyclonal sera occurs through alterations at several different epitopes, generally resulting from single amino acid substitutions which influence envelope conformation. Experiments on a double mutant showed that the combination of both mutations is not additive, suggesting that these variants utilized alternate pathways to elicit similar alterations of the HIV-1 envelope structure.

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“…Epitope mapping by ELISA with HxBc2 gp120 mutants. ELISA binding studies with HxBc2 gp120 mutants were performed as described previously (35,37), with the addition of the following mutants to the test panel: the mutant with a K-to-A substitution at position 59 (59K/A), 64E/A, 67N/A, 97K/…”

Section: Methodsmentioning

confidence: 99%

Human monoclonal antibody 2G12 defines a distinctive neutralization epitope on the gp120 glycoprotein of human immunodeficiency virus type 1

Trkola

Purtscher

Muster

et al. 1996

J Virol

Self Cite

1,042

400

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We have isolated and characterized human monoclonal antibody 2G12 to the gp120 surface glycoprotein of human immunodeficiency virus type 1 (HIV-1). This antibody potently and broadly neutralizes primary and T-cell line-adapted clade B strains of HIV-1 in a peripheral blood mononuclear cell-based assay and inhibits syncytium formation in the AA-2 cell line. Furthermore, 2G12 possesses neutralizing activity against strains from clade A but not from clade E. Complement-and antibody-dependent cellular cytotoxicity-activating functions of 2G12 were also defined. The gp120 epitope recognized by 2G12 was found to be distinctive; binding of 2G12 to LAI recombinant gp120 was abolished by amino acid substitutions removing N-linked carbohydrates in the C2, C3, V4, and C4 regions of gp120. This gp120 mutant recognition pattern has not previously been observed, indicating that the 2G12 epitope is unusual. Consistent with this, antibodies able to block 2G12 binding to recombinant gp120 were not detected in significant quantities in 16 HIV-positive human serum samples.

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Immunological evidence for interactions between the first, second, and fifth conserved domains of the gp120 surface glycoprotein of human immunodeficiency virus type 1

Abstract: We have used a combination of genetic and immunological techniques to explore how amino acid substitutions in the second conserved (C2) domain of gpl20 from human immunodeficiency virus type 1 (HIV-1) affect the conformation of the protein. It was reported previously (R. L.

Cited by 83 publications

References 41 publications

Sensitivity of human immunodeficiency virus to bicyclam derivatives is influenced by the three-dimensional structure of gp120

Sensitivity of human immunodeficiency virus to bicyclam derivatives is influenced by the three-dimensional structure of gp120

Resistance of human immunodeficiency virus type 1 to neutralization by natural antisera occurs through single amino acid substitutions that cause changes in antibody binding at multiple sites

Human monoclonal antibody 2G12 defines a distinctive neutralization epitope on the gp120 glycoprotein of human immunodeficiency virus type 1

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