Interferon-inducible mechanism of dendritic cell-mediated HIV-1 dissemination is dependent on Siglec-1/CD169

• Published in: PLoS pathogens Vol. 9; no. 4; p. e1003291
• Main Authors: Puryear, Wendy Blay, Akiyama, Hisashi, Geer, Suzanne D, Ramirez, Nora P, Yu, Xinwei, Reinhard, Björn M, Gummuluru, Suryaram
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-04-2013; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; AIDS; Animals; Biology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; Cell Line; Cloning; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dendritic Cells - virology; Down-Regulation; Experiments; Flow cytometry; G(M3) Ganglioside - genetics; G(M3) Ganglioside - metabolism; Genetic aspects; HEK293 Cells; HIV; HIV infection; HIV Infections - immunology; HIV Infections - metabolism; HIV Infections - virology; HIV-1 - immunology; HIV-1 - physiology; Host-parasite relationships; Human immunodeficiency virus; Humans; Interferon; Interferon-alpha - metabolism; Lipids; Lymphocytes; Medicine; Mice; Polyclonal antibodies; Properties; Rats; RNA Interference; Rodents; Sialic Acid Binding Ig-like Lectin 1 - genetics; Sialic Acid Binding Ig-like Lectin 1 - metabolism; Signal Transduction; United States
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1003291

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.