title: Glycosylation inhibitors and neuraminidase enhance human immunodeficiency virus type 1 binding and neutralization by mannose-binding lectin.
abstract: Mannose-binding lectin (MBL), a C-type lectin component of the human innate immune system, binds to the gp120 envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1). The objective of this study was to assess the effects of inhibitors of endoplasmic reticulum glucosidases and Golgi mannosidase as well as neuraminidase (NA) on the interaction between HIV and MBL. Production of HIV in the presence of the mannosidase I inhibitor deoxymannojirimycin (dMM) significantly enhanced binding of HIV to MBL and increased MBL neutralization of an M-tropic HIV primary isolate. In contrast, culturing HIV in the presence of alpha-glucosidase I and II inhibitors castanospermine and deoxynojirimycin only slightly affected virus binding and neutralization by MBL. Removal of sialic acid from HIV by NA also significantly enhanced virus binding and neutralization by MBL. Treatment of virus grown in the presence of dMM with endoglycosidase F1 substantially reduced binding to MBL, indicating that dMM increased MBL binding by increasing high-mannose carbohydrates on the virus. In contrast, endoglycosidase F1 did not decrease the MBL interaction with NA-treated virus, suggesting that NA exposed novel MBL binding sites. Treatment with dMM increased the immunocapture of HIV by monoclonal antibodies 2F5 and 2G12, indicating that altering the glycosylation of viral glycoproteins increases the accessibility or reactivity of some epitopes. This study shows that specific alterations of the N-linked carbohydrates on HIV gp120/gp41 can enhance MBL-mediated neutralization of virus by strengthening the interaction of HIV-1 with MBL.
authors.affiliation: Department of Immunology/Microbiology, Rush-Presbyterian-St Luke's Medical Center, 1563 W. Congress Parkway, Chicago, IL 60612, USA.
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Hart
authors.affiliation: Department of Immunology/Microbiology, Rush-Presbyterian-St Luke's Medical Center, 1563 W. Congress Parkway, Chicago, IL 60612, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Saifuddin
authors.affiliation: Department of Immunology/Microbiology, Rush-Presbyterian-St Luke's Medical Center, 1563 W. Congress Parkway, Chicago, IL 60612, USA.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Spear
mesh_terms: D017485:1-Deoxynojirimycin / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005959:Glucosidases / Q000037:antagonists & inhibitors; D006031:Glycosylation / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007212:Indolizines / Q000494:pharmacology; D037601:Mannose-Binding Lectin / Q000378:metabolism*; D008361:Mannosidases / Q000037:antagonists & inhibitors; D009439:Neuraminidase / Q000378:metabolism / Q000494:pharmacology*; D009500:Neutralization Tests; D054836:Indolizidines
chemical_list: D017485:1-Deoxynojirimycin; D004791:Enzyme Inhibitors; D005959:Glucosidases; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D007212:Indolizines; D037601:Mannose-Binding Lectin; D008361:Mannosidases; D009439:Neuraminidase; C046090:mannosyl-oligosaccharide 1,2-alpha-mannosidase; C037806:castanospermine; D054836:Indolizidines