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

Fabien P. Blanchet (1) , Romaine Stalder (2) , Magdalena Czubala (3) , Martin Lehmann (4) , Laura Rio , Bastien Mangeat (5) , Vincent Piguet (6)

1 IRIM - Institut de Recherche en Infectiologie de Montpellier
2 Departments of Dermatology and Venereology, Microbiology and Molecular Medicine
3 School of Medicine [Cardiff]
4 FMP - Leibniz Forschungsinstitut für Molekulare Pharmakolgie = Leibniz Institute for Molecular Pharmacology [Berlin, Allemagne]
5 EPFL - Ecole Polytechnique Fédérale de Lausanne
6 Division of Infection and Immunity

Background : Dendritic cells and their subsets, located at mucosal surfaces, are among the first immune cells toencounter 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 primarycells such as macrophages. However, BST-2/tetherin does not efficiently restrict HIV-1 infection in immaturedendritic cells.Results : We now report that BST-2/tetherin expression in myeloid (myDC) and monocyte-derived dendritic cells (DC)can be significantly up-regulated by IFN-αtreatment and TLR-4 engagement with LPS. In contrast to HeLa or 293Tcells, infectious HIV-1 release in immature DC and IFN-α–matured DC was only modestly affected in the absence ofVpu compared to wild-type viruses. Strikingly, immunofluorescence analysis revealed that BST-2/tetherin was excludedfrom HIV containing tetraspanin-enriched microdomains (TEMs) in both immature DC and IFN-α–matured DC. Incontrast, in LPS-mediated mature DC, BST-2/tetherin exerted a significant restriction in transfer of HIV-1 infection toCD4+T cells. Additionally, LPS, but not IFN-αstimulation of immature DC, leads to a dramatic redistribution of cellularrestriction factors to the TEM as well as at the virological synapse between DC and CD4+Tcells. Conclusions : In conclusion, we demonstrate that TLR-4 engagement in immature DC significantly up-regulates theintrinsic 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, hasimplications in the design of antiviral therapeutic strategies.

Mots clés: Human immunodeficiency virus-1 (HIV-1); Bone marrow stromal cell antigen-2 (BST-2)/tetherin; Dendriticcells; Lipopolysaccharide (LPS); Interferon-alpha (IFN-α)

Domaines: Biologie cellulaire; Immunologie; Virologie; Immunité innée; Immunité adaptative

Fabien P. Blanchet, Romaine Stalder, Magdalena Czubala, Martin Lehmann, Laura Rio, et al.. 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. Retrovirology, 2013, 10 (1), pp.6. ⟨10.1186/1742-4690-10-6⟩. ⟨hal-02352285⟩