Mutations at the CXCR4 interaction sites for AMD3100 influence anti-CXCR4 antibody binding and HIV-1 entry

Sigrid Hatse; Katrien Princen; Kurt Vermeire; Lars-Ole Gerlach; Mette M Rosenkilde; Thue W Schwartz; Gary Bridger; Erik De Clercq; Dominique Schols

Mutations at the CXCR4 interaction sites for AMD3100 influence anti-CXCR4 antibody binding and HIV-1 entry

Sigrid Hatse, Katrien Princen, Kurt Vermeire, Lars-Ole Gerlach, Mette M Rosenkilde, Thue W Schwartz, Gary Bridger, Erik De Clercq, Dominique Schols

Department of Neuroscience

41 Citations (Scopus)

Abstract

The interaction of the CXCR4 antagonist AMD3100 with its target is greatly influenced by specific aspartate residues in the receptor protein, including Asp(171) and Asp(262). We have now found that aspartate-to-asparagine substitutions at these positions differentially affect the binding of four different anti-CXCR4 monoclonal antibodies as well as the infectivity of diverse human immunodeficiency virus type 1 (HIV-1) strains and clinical isolates. Mutation of Asp(262) strongly decreased the coreceptor efficiency of CXCR4 for wild-type but not for AMD3100-resistant HIV-1 NL4.3. Thus, resistance of HIV-1 NL4.3 to AMD3100 is associated with a decreased dependence of the viral gp120 on Asp(262) of CXCR4, pointing to a different mode of interaction of wild-type versus AMD3100-resistant virus with CXCR4.

Original language	English
Journal	FEBS Letters
Volume	546
Issue number	2-3
Pages (from-to)	300-6
Number of pages	6
ISSN	0014-5793
Publication status	Published - 2003

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@article{925e1b8074c211dbbee902004c4f4f50,

title = "Mutations at the CXCR4 interaction sites for AMD3100 influence anti-CXCR4 antibody binding and HIV-1 entry",

abstract = "The interaction of the CXCR4 antagonist AMD3100 with its target is greatly influenced by specific aspartate residues in the receptor protein, including Asp(171) and Asp(262). We have now found that aspartate-to-asparagine substitutions at these positions differentially affect the binding of four different anti-CXCR4 monoclonal antibodies as well as the infectivity of diverse human immunodeficiency virus type 1 (HIV-1) strains and clinical isolates. Mutation of Asp(262) strongly decreased the coreceptor efficiency of CXCR4 for wild-type but not for AMD3100-resistant HIV-1 NL4.3. Thus, resistance of HIV-1 NL4.3 to AMD3100 is associated with a decreased dependence of the viral gp120 on Asp(262) of CXCR4, pointing to a different mode of interaction of wild-type versus AMD3100-resistant virus with CXCR4.",

author = "Sigrid Hatse and Katrien Princen and Kurt Vermeire and Lars-Ole Gerlach and Rosenkilde, {Mette M} and Schwartz, {Thue W} and Gary Bridger and {De Clercq}, Erik and Dominique Schols",

note = "Keywords: Amino Acid Sequence; Binding Sites; Flow Cytometry; HIV-1; Heterocyclic Compounds; Humans; Membrane Fusion; Molecular Sequence Data; Mutation; Receptors, CXCR4; Tumor Cells, Cultured",

year = "2003",

language = "English",

volume = "546",

pages = "300--6",

journal = "F E B S Letters",

issn = "0014-5793",

publisher = "JohnWiley & Sons Ltd",

number = "2-3",

}

TY - JOUR

T1 - Mutations at the CXCR4 interaction sites for AMD3100 influence anti-CXCR4 antibody binding and HIV-1 entry

AU - Hatse, Sigrid

AU - Princen, Katrien

AU - Vermeire, Kurt

AU - Gerlach, Lars-Ole

AU - Rosenkilde, Mette M

AU - Schwartz, Thue W

AU - Bridger, Gary

AU - De Clercq, Erik

AU - Schols, Dominique

N1 - Keywords: Amino Acid Sequence; Binding Sites; Flow Cytometry; HIV-1; Heterocyclic Compounds; Humans; Membrane Fusion; Molecular Sequence Data; Mutation; Receptors, CXCR4; Tumor Cells, Cultured

PY - 2003

Y1 - 2003

N2 - The interaction of the CXCR4 antagonist AMD3100 with its target is greatly influenced by specific aspartate residues in the receptor protein, including Asp(171) and Asp(262). We have now found that aspartate-to-asparagine substitutions at these positions differentially affect the binding of four different anti-CXCR4 monoclonal antibodies as well as the infectivity of diverse human immunodeficiency virus type 1 (HIV-1) strains and clinical isolates. Mutation of Asp(262) strongly decreased the coreceptor efficiency of CXCR4 for wild-type but not for AMD3100-resistant HIV-1 NL4.3. Thus, resistance of HIV-1 NL4.3 to AMD3100 is associated with a decreased dependence of the viral gp120 on Asp(262) of CXCR4, pointing to a different mode of interaction of wild-type versus AMD3100-resistant virus with CXCR4.

AB - The interaction of the CXCR4 antagonist AMD3100 with its target is greatly influenced by specific aspartate residues in the receptor protein, including Asp(171) and Asp(262). We have now found that aspartate-to-asparagine substitutions at these positions differentially affect the binding of four different anti-CXCR4 monoclonal antibodies as well as the infectivity of diverse human immunodeficiency virus type 1 (HIV-1) strains and clinical isolates. Mutation of Asp(262) strongly decreased the coreceptor efficiency of CXCR4 for wild-type but not for AMD3100-resistant HIV-1 NL4.3. Thus, resistance of HIV-1 NL4.3 to AMD3100 is associated with a decreased dependence of the viral gp120 on Asp(262) of CXCR4, pointing to a different mode of interaction of wild-type versus AMD3100-resistant virus with CXCR4.

M3 - Journal article

C2 - 12832058

SN - 0014-5793

VL - 546

SP - 300

EP - 306

JO - F E B S Letters

JF - F E B S Letters

IS - 2-3

ER -

Mutations at the CXCR4 interaction sites for AMD3100 influence anti-CXCR4 antibody binding and HIV-1 entry

Abstract

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