The role of N-glycosylation sites on the CXCR4 receptor for CXCL-12 binding and signaling and X4 HIV-1 viral infectivity.
The chemokine receptor CXCR4 functions as one of the HIV-1 coreceptors and can be considered as an attractive target for the development of novel anti-HIV drugs. Here, we investigated the effect of its two known N-glycosylation sites g1 (NYT) and g2 (NVS) on the antiviral potential of several classes of entry inhibitors. The lack of g1 clearly affected the binding of the amino-terminal directed 2B11 mAb, but not the 12G5 mAb. No dramatic effects on CXCL-12 binding and CXCL-12-induced intracellular calcium responses were observed. Importantly, the anti-HIV-1 activity and antagonistic activity of the prototype compound of CXCR4 inhibitors, AMD3100, were not affected by the presence or absence of the CXCR4 N-glycans. Since CXCR4 N-glycans play a less important role in viral entry compared to the N-glycans on the HIV envelope, cells expressing CXCR4 N-glycosylation mutants might be no relevant alternative to allow HIV-1 escape from antivirals.
Huskens
Dana
D
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Princen
Katrien
K
Schreiber
Michael
M
Schols
Dominique
D
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000502:physiology; D019380:Anti-HIV Agents / Q000494:pharmacology; D000906:Antibodies / Q000378:metabolism / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology; D001596:Benzylamines; D001665:Binding Sites / Q000502:physiology; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism* / Q000494:pharmacology; D000080027:Cyclams; D024882:Drug Resistance, Viral; D006031:Glycosylation; D023581:HIV Fusion Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000472:pathogenicity* / Q000502:physiology*; D006571:Heterocyclic Compounds / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D037102:Lectins / Q000378:metabolism / Q000494:pharmacology; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015728:Receptors, HIV / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014774:Virulence; D014779:Virus Replication
D000596:Amino Acids; D019380:Anti-HIV Agents; D000906:Antibodies; D000911:Antibodies, Monoclonal; D001596:Benzylamines; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D000080027:Cyclams; D023581:HIV Fusion Inhibitors; D006571:Heterocyclic Compounds; D037102:Lectins; D019718:Receptors, CXCR4; D015728:Receptors, HIV; C088327:plerixafor