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PLoS Pathog. 2016 Apr 15;12(4):e1005553. doi: 10.1371/journal.ppat.1005553. eCollection 2016 Apr.

CD4 Receptor is a Key Determinant of Divergent HIV-1 Sensing by Plasmacytoid Dendritic Cells.

Author information

1
Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
2
Division of Hematology and Oncology, Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
3
Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
4
Microscopy Shared Resource Facility, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
5
Department of Pediatrics, the University of Chicago, Chicago, Illinois, United States of America.

Abstract

Plasmacytoid dendritic cells (pDC) are innate immune cells that sense viral nucleic acids through endosomal Toll-like receptor (TLR) 7/9 to produce type I interferon (IFN) and to differentiate into potent antigen presenting cells (APC). Engagement of TLR7/9 in early endosomes appears to trigger the IRF7 pathway for IFN production whereas engagement in lysosomes seems to trigger the NF-κB pathway for maturation into APC. We showed previously that HIV-1 (HIV) localizes predominantly to early endosomes, not lysosomes, and mainly stimulate IRF7 rather than NF-κB signaling pathways in pDC. This divergent signaling may contribute to disease progression through production of pro-apoptotic and pro-inflammatory IFN and inadequate maturation of pDCs. We now demonstrate that HIV virions may be re-directed to lysosomes for NF-κB signaling by either pseudotyping HIV with influenza hemagglutinin envelope or modification of CD4 mediated-intracellular trafficking. These data suggest that HIV envelope-CD4 receptor interactions drive pDC activation toward an immature IFN producing phenotype rather than differentiation into a mature dendritic cell phenotype.

PMID:
27082754
PMCID:
PMC4833349
DOI:
10.1371/journal.ppat.1005553
[Indexed for MEDLINE]
Free PMC Article

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