title: HIV-1 transmission by dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) is regulated by determinants in the carbohydrate recognition domain that are absent in liver/lymph node-SIGN (L-SIGN).
abstract: In this study, we identify determinants in dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) necessary for human immunodeficiency virus, type 1 (HIV-1), transmission. Although human B cell lines expressing DC-SIGN efficiently capture and transmit HIV-1 to susceptible target cells, cells expressing the related molecule liver/lymph node-specific ICAM-3-grabbing nonintegrin (L-SIGN) do not. To understand the differences between DC-SIGN and L-SIGN that affect HIV-1 interactions, we developed Raji B cell lines expressing different DC-SIGN/L-SIGN chimeras. Testing of the chimeras demonstrated that replacement of the DC-SIGN carbohydrate-recognition domain (CRD) with that of L-SIGN was sufficient to impair virus binding and prevent transmission. Conversely, the ability to bind and transmit HIV-1 was conferred to L-SIGN chimeras containing the DC-SIGN CRD. We identified Trp-258 in the DC-SIGN CRD to be essential for HIV-1 transmission. Although introduction of a K270W mutation at the same position in L-SIGN was insufficient for HIV-1 binding, an L-SIGN mutant molecule with K270W and a C-terminal DC-SIGN CRD subdomain transmitted HIV-1. These data suggest that DC-SIGN structural elements distinct from the oligosaccharide-binding site are required for HIV-1 glycoprotein selectivity.
authors.affiliation: HIV Drug Resistance Program, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
authors.forename: Nancy P Y
authors.initials: NP
authors.lastname: Chung
authors.forename: Sabine K J
authors.initials: SK
authors.lastname: Breun
authors.forename: Arman
authors.initials: A
authors.lastname: Bashirova
authors.forename: Joerg G
authors.initials: JG
authors.lastname: Baumann
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Martin
authors.forename: Jaideep M
authors.initials: JM
authors.lastname: Karamchandani
authors.forename: Jason W
authors.initials: JW
authors.lastname: Rausch
authors.forename: Stuart F J
authors.initials: SF
authors.lastname: Le Grice
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.forename: Vineet N
authors.initials: VN
authors.lastname: Kewalramani
mesh_terms: D000483:Alleles; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D050260:Carbohydrate Metabolism; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000378:metabolism* / Q000635:transmission*; D015497:HIV-1; D006801:Humans; D037102:Lectins / Q000378:metabolism; D037181:Lectins, C-Type / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D037102:Lectins; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C433029:CLEC4M protein, human