title: Interferon-inducible mechanism of dendritic cell-mediated HIV-1 dissemination is dependent on Siglec-1/CD169.
abstract: Human immunodeficiency virus type 1 (HIV-1) interactions with myeloid dendritic cells (DCs) can result in virus dissemination to CD4⁺ T cells via a trans infection pathway dependent on virion incorporation of the host cell derived glycosphingolipid (GSL), GM3. The mechanism of DC-mediated trans infection is extremely efficacious and can result in infection of multiple CD4⁺ T cells as these cells make exploratory contacts on the DC surface. While it has long been appreciated that activation of DCs with ligands that induce type I IFN signaling pathway dramatically enhances DC-mediated T cell trans infection, the mechanism by which this occurs has remained unclear until now. Here, we demonstrate that the type I IFN-inducible Siglec-1, CD169, is the DC receptor that captures HIV in a GM3-dependent manner. Selective downregulation of CD169 expression, neutralizing CD169 function, or depletion of GSLs from virions, abrogated DC-mediated HIV-1 capture and trans infection, while exogenous expression of CD169 in receptor-naïve cells rescued GSL-dependent capture and trans infection. HIV-1 particles co-localized with CD169 on DC surface immediately following capture and subsequently within non-lysosomal compartments that redistributed to the DC--T cell infectious synapses upon initiation of T cell contact. Together, these findings describe a novel mechanism of pathogen parasitization of host encoded cellular recognition machinery (GM3--CD169 interaction) for DC-dependent HIV dissemination.
authors.affiliation: Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Wendy Blay
authors.initials: WB
authors.lastname: Puryear
authors.forename: Hisashi
authors.initials: H
authors.lastname: Akiyama
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Geer
authors.forename: Nora P
authors.initials: NP
authors.lastname: Ramirez
authors.forename: Xinwei
authors.initials: X
authors.lastname: Yu
authors.forename: Björn M
authors.initials: BM
authors.lastname: Reinhard
authors.forename: Suryaram
authors.initials: S
authors.lastname: Gummuluru
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D015536:Down-Regulation; D005679:G(M3) Ganglioside / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000276:immunology / Q000502:physiology*; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D051379:Mice; D034622:RNA Interference; D051381:Rats; D063267:Sialic Acid Binding Ig-like Lectin 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D005679:G(M3) Ganglioside; D016898:Interferon-alpha; D063267:Sialic Acid Binding Ig-like Lectin 1