title: Functional evaluation of DC-SIGN monoclonal antibodies reveals DC-SIGN interactions with ICAM-3 do not promote human immunodeficiency virus type 1 transmission.
abstract: DC-SIGN, a type II membrane-spanning C-type lectin that is expressed on the surface of dendritic cells (DC), captures and promotes human and simian immunodeficiency virus (HIV and SIV) infection of CD4(+) T cells in trans. To better understand the mechanism of DC-SIGN-mediated virus transmission, we generated and functionally evaluated a panel of seven monoclonal antibodies (MAbs) against DC-SIGN family molecules. Six of the MAbs reacted with myeloid-lineage DC, whereas one MAb preferentially bound DC-SIGNR/L-SIGN, a homolog of DC-SIGN. Characterization of hematopoietic cells also revealed that stimulation of monocytes with interleukin-4 (IL-4) or IL-13 was sufficient to induce expression of DC-SIGN. All DC-SIGN-reactive MAbs competed with intercellular adhesion molecule 3 (ICAM-3) for adhesion to DC-SIGN and blocked HIV-1 transmission to T cells that was mediated by THP-1 cells expressing DC-SIGN. Similar but less efficient MAb blocking of DC-mediated HIV-1 transmission was observed, indicating that HIV-1 transmission to target cells via DC may not be dependent solely on DC-SIGN. Attempts to neutralize DC-SIGN capture and transmission of HIV-1 with soluble ICAM-3 prophylaxis were limited in success, with a maximal inhibition of 60%. In addition, disrupting DC-SIGN/ICAM-3 interactions between cells with MAbs did not impair DC-SIGN-mediated HIV-1 transmission. Finally, forced expression of ICAM-3 on target cells did not increase their susceptibility to HIV-1 transmission mediated by DC-SIGN. While these findings do not discount the role of intercellular contact in facilitating HIV-1 transmission, our in vitro data indicate that DC-SIGN interactions with ICAM-3 do not promote DC-SIGN-mediated virus transmission.
authors.affiliation: HIV Drug Resistance Program, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Martin
authors.forename: Rosemay
authors.initials: R
authors.lastname: Vazeux
authors.forename: Derya
authors.initials: D
authors.lastname: Unutmaz
authors.forename: Vineet N
authors.initials: VN
authors.lastname: KewalRamani
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000378:metabolism*; D001667:Binding, Competitive; D015815:Cell Adhesion Molecules; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D015658:HIV Infections / Q000635:transmission* / Q000821:virology; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D037102:Lectins / Q000276:immunology / Q000378:metabolism*; D037181:Lectins, C-Type; D051379:Mice; D009000:Monocytes; D009500:Neutralization Tests; D011946:Receptors, Antigen / Q000276:immunology; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism*; D011991:Receptors, Virus / Q000276:immunology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D015815:Cell Adhesion Molecules; D037102:Lectins; D037181:Lectins, C-Type; D011946:Receptors, Antigen; D011956:Receptors, Cell Surface; D011991:Receptors, Virus; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C433029:CLEC4M protein, human; C483616:ICAM3 protein, human