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.
Highlights
Myeloid dendritic cells (DCs) are potent antigen presenting cells that monitor their immediate environment for invading pathogens
To identify the DC-receptor required for GM3-dependent Human immunodeficiency virus type 1 (HIV-1) capture, primary peripheral blood CD14+ monocytes, immature DCs, and DCs activated with TLR2 (Pam3CysK4), TLR3 (poly(I:C)), or TLR4 (E. coli LPS) agonists, or stimulated with the cytokines, IFNa or TNFa were tested for their ability to capture Env-deficient HIV-1 Gag-eGFP virus like particles (VLPs)
Direct exposure of immature DCs to IFNa alone but not TNFa, resulted in a similar level of VLP capture to that observed with LPS or poly(I:C)-stimulated DCs (Figure 1A), suggesting HIV-1 capture by DCs is dependent on the presence of an IFNainducible factor
Summary
Myeloid dendritic cells (DCs) are potent antigen presenting cells that monitor their immediate environment for invading pathogens. The ability of these sentinel DCs to sample and process antigen, and present processed antigen to naıve T cells is critical to the development of effective adaptive immune responses. DCdependent HIV-1 trans infection of CD4+ T cells is an efficacious HIV dissemination mechanism [1,2] that has been hypothesized to provide virus particles evasion from host innate and adaptive immune responses [3]. HIV-1 capture by DCs and access to the DC-dependent trans infection pathway has long been thought to be exclusively dependent on the interactions of the mannosylated virus envelope glycoprotein gp120 with C-type lectin receptors (CLRs) [4], such as dendritic cell-specific intercellular adhesion molecule-3binding nonintegrin (DC-SIGN) [5]. In addition to HIV-1 capture, virus targeting to tetraspanin protein positive non-lysosomal compartments that allow for virus persistence and evasion from lysosomal degradation pathways in DCs [6,7,8] has been reported to be dependent on DC-SIGN [9,10]
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