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

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O'Brien M, Manches O, Wilen C, Gopal R, Huq R, Wu V, Sunseri N, Bhardwaj N,


O'Brien M, Manches O, Wilen C, Gopal R, Huq R, Wu V, Sunseri N, Bhardwaj N, (click to view)

O'Brien M, Manches O, Wilen C, Gopal R, Huq R, Wu V, Sunseri N, Bhardwaj N,

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PLoS pathogens 2016 4 1512(4) e1005553 doi 10.1371/journal.ppat.1005553

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.

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