Email updates

Keep up to date with the latest news and content from Retrovirology and BioMed Central.

Open Access Highly Accessed Research

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 Blanchet1, Romaine Stalder2, Magdalena Czubala1, Martin Lehmann2, Laura Rio2, Bastien Mangeat12 and Vincent Piguet1*

Author Affiliations

1 Department of Dermatology and Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, 3rd Floor, Glamorgan house, Heath Park, Wales, Cardiff, CF14 4XN, United Kingdom

2 Dept. of Microbiology and Molecular Medicine, Medical School of Geneva, Geneva, Switzerland

For all author emails, please log on.

Retrovirology 2013, 10:6  doi:10.1186/1742-4690-10-6

Published: 11 January 2013

Abstract

Background

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.

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-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.

Conclusions

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.

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