TLR-4 engagement of dendritic cells confers a BST-2/tetherin-mediated restriction of HIV-1 infection to CD4+ T cells across the virological synapse

• Published in: Retrovirology Vol. 10; no. 1; p. 6
• Main Authors: Blanchet, Fabien P, Stalder, Romaine, Czubala, Magdalena, Lehmann, Martin, Rio, Laura, Mangeat, Bastien, Piguet, Vincent
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 11.01.2013; BioMed Central; BMC
• Subjects: Adaptive immunology; Antigens, CD - genetics; Antigens, CD - immunology; Biological response modifiers; Bone marrow stromal cell antigen-2 (BST-2)/tetherin; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; Cell Differentiation; Cellular Biology; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - virology; Flow cytometry; Gene Expression Regulation - immunology; GPI-Linked Proteins - genetics; GPI-Linked Proteins - immunology; Health aspects; HeLa Cells; HIV (Viruses); HIV-1 - drug effects; HIV-1 - immunology; Human immunodeficiency virus-1 (HIV-1); Humans; Immunological Synapses - drug effects; Immunological Synapses - virology; Immunology; Infections; Innate immunity; Interferon; Interferon-alpha (IFN-α); Interferon-alpha - pharmacology; Life Sciences; Lipopolysaccharide (LPS); Lipopolysaccharides - pharmacology; Lymphocytes; Macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - virology; Microbiology and Parasitology; Microscopy; Mitogens; Monocytes - drug effects; Monocytes - immunology; Monocytes - virology; Primary Cell Culture; Proteins; Signal Transduction; T cells; Tetraspanins - genetics; Tetraspanins - immunology; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - immunology; Virion - drug effects; Virion - immunology; Virology; Virus Release - drug effects; Virus Replication - drug effects; Wound healing; Canada; Human immunodeficiency virus-1 (HIV-1); Dendriticcells; Interferon-alpha (IFN-α); Bone marrow stromal cell antigen-2 (BST-2)/tetherin; Lipopolysaccharide (LPS)
• ISSN: 1742-4690; 1742-4690
• DOI: 10.1186/1742-4690-10-6

Dendritic cells and their subsets, located at mucosal surfaces, are among the first immune cells to encounter disseminating pathogens. The cellular restriction factor BST-2/tetherin (also known as CD317 or HM1.24) potently restricts HIV-1 release by retaining viral particles at the cell surface in many cell types, including primary cells such as macrophages. However, BST-2/tetherin does not efficiently restrict HIV-1 infection in immature dendritic cells. We now report that BST-2/tetherin expression in myeloid (myDC) and monocyte-derived dendritic cells (DC) can be significantly up-regulated by IFN-α treatment and TLR-4 engagement with LPS. In contrast to HeLa or 293T cells, infectious HIV-1 release in immature DC and IFN-α-matured DC was only modestly affected in the absence of Vpu compared to wild-type viruses. Strikingly, immunofluorescence analysis revealed that BST-2/tetherin was excluded from HIV containing tetraspanin-enriched microdomains (TEMs) in both immature DC and IFN-α-matured DC. In contrast, in LPS-mediated mature DC, BST-2/tetherin exerted a significant restriction in transfer of HIV-1 infection to CD4+ T cells. Additionally, LPS, but not IFN-α stimulation of immature DC, leads to a dramatic redistribution of cellular restriction factors to the TEM as well as at the virological synapse between DC and CD4+ T cells. In conclusion, we demonstrate that TLR-4 engagement in immature DC significantly up-regulates the intrinsic antiviral activity of BST-2/tetherin, during cis-infection of CD4+ T cells across the DC/T cell virological synapse. Manipulating the function and potency of cellular restriction factors such as BST-2/tetherin to HIV-1 infection, has implications in the design of antiviral therapeutic strategies.