Interferon-Inducible Mechanism of Dendritic Cell-Mediated HIV-1 Dissemination Is Dependent on Siglec-1/CD169

Autor: Suryaram Gummuluru, Xinwei Yu, Björn M. Reinhard, Nora P. Ramirez, Wendy B. Puryear, Suzanne D. Geer, Hisashi Akiyama
Rok vydání: 2013
Předmět:
CD4-Positive T-Lymphocytes
Sialic Acid Binding Ig-like Lectin 1
Cellular differentiation
HIV Infections
Mice
0302 clinical medicine
Interferon
Molecular Cell Biology
lcsh:QH301-705.5
0303 health sciences
3. Good health
Infectious Diseases
medicine.anatomical_structure
030220 oncology & carcinogenesis
Medicine
RNA Interference
lipids (amino acids
peptides
and proteins)
Signal transduction
Signal Transduction
Research Article
medicine.drug
lcsh:Immunologic diseases. Allergy
T cell
Immunology
Down-Regulation
Biology
Microbiology
Cell Line
03 medical and health sciences
Virology
Genetics
medicine
Animals
G(M3) Ganglioside
Humans
Molecular Biology
030304 developmental biology
HEK 293 cells
Interferon-alpha
SIGLEC
Dendritic Cells
Dendritic cell
Rats
HEK293 Cells
lcsh:Biology (General)
Cell culture
HIV-1
Parasitology
lcsh:RC581-607
Zdroj: PLoS Pathogens
PLoS Pathogens, Vol 9, Iss 4, p e1003291 (2013)
ISSN: 1553-7374
DOI: 10.1371/journal.ppat.1003291
Popis: 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.
Author Summary Dendritic cells (DCs) are one of the initial cellular targets of HIV-1 and can play a crucial role in determining the course of virus infection in vivo. While sentinel functions of DCs are essential for establishment of an antiviral state, HIV-1 can subvert DC function for its dissemination. One of the mechanisms by which DCs can mediate virus spread is via the trans infection pathway whereby DCs capture HIV-1 particles and retain them in an infectious state without getting infected, and pass these infectious particles to CD4+ T cells upon initiation of cellular contacts. In this report, we demonstrate that expression of Siglec-1or CD169, on DC surface is responsible for capture of HIV-1 particles by binding the ganglioside, GM3, present in the virion lipid bilayer. This interaction between CD169 and GM3 targets captured virus particles to non-degradative compartments and resulted in retention of virus particle infectivity within DCs. Upon initiation of T cell contacts with virus-laden DCs, HIV-1 particles were trafficked to the DC – T synaptic junctions and transferred to T cells for establishment of productive infection. These studies define a novel host-encoded receptor – ligand interaction that drives HIV-1 dissemination and can be used for development of novel anti-viral therapeutics.
Databáze: OpenAIRE
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