The alpha-glucosidase inhibitor 1-deoxynojirimycin blocks human immunodeficiency virus envelope glycoprotein-mediated membrane fusion at the CXCR4 binding step.
1-Deoxynojirimycin (DNM) is a saccharide decoy that inhibits cellular alpha-glucosidase I-II activity. Treatment by DNM of human immunodeficiency virus (HIV)-infected lymphocyte cultures inhibits virus spread. The functional properties of the membrane-associated Env glycoprotein (Env) modified in the presence of DNM remain unclear because previous reports on this subject have essentially used recombinant soluble Envs whose properties differ notably from those of Env anchored on the surface of the virus. To model virus-associated Env synthesized in the presence of DNM, native Env was expressed at the surface of mammalian cells treated with DNM. As expected, its glycosylation pattern was altered in the presence of the inhibitor. Env was found able to bind CD4, whereas its ability to induce membrane fusion was abolished. The immunoreactivity of regions involved in interactions of Env with CXCR4 (V1, V2, C2, and V3) was modified and Env displayed altered interaction with this coreceptor. These results are consistent with the inhibition by DNM of virus entry at the Env/coreceptor interaction step. Finally, preliminary data indicate that suboptimal concentrations of DNM and natural or synthetic CXCR4 ligands used in combination potently inhibit the Env-mediated membrane fusion process. Altogether, our results suggest that DNM and its analogs deserve further investigation as anti-HIV agents in combination with experimental compounds targeting CXCR4 to inhibit each partner of this crucial step of HIV entry.
Papandréou
Marie-Jeanne
MJ
Centre National de la Recherche Scientifique, Faculté de Médecine Nord, Marseille, France.
Barbouche
Rym
R
Guieu
Régis
R
Kieny
Marie Paule
MP
Fenouillet
Emmanuel
E
D017485:1-Deoxynojirimycin / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D015704:CD4 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D004338:Drug Combinations; D065089:Glycoside Hydrolase Inhibitors; D006031:Glycosylation / Q000187:drug effects; D006678:HIV / Q000187:drug effects* / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008561:Membrane Fusion / Q000187:drug effects*; D051379:Mice; D019718:Receptors, CXCR4 / Q000819:agonists / Q000378:metabolism; D000520:alpha-Glucosidases / Q000378:metabolism
D000998:Antiviral Agents; D015704:CD4 Antigens; D004338:Drug Combinations; D065089:Glycoside Hydrolase Inhibitors; D015699:HIV Envelope Protein gp120; D008024:Ligands; D019718:Receptors, CXCR4; D017485:1-Deoxynojirimycin; D000520:alpha-Glucosidases