title: CD4 Receptor is a Key Determinant of Divergent HIV-1 Sensing by Plasmacytoid Dendritic Cells.
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.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Meagan
authors.initials: M
authors.lastname: O'Brien
authors.affiliation: 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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Manches
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Craig
authors.initials: C
authors.lastname: Wilen
authors.affiliation: 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.
authors.forename: Ramya
authors.initials: R
authors.lastname: Gopal
authors.affiliation: Microscopy Shared Resource Facility, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Rumana
authors.initials: R
authors.lastname: Huq
authors.affiliation: 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.
authors.forename: Vernon
authors.initials: V
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, the University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Nicole
authors.initials: N
authors.lastname: Sunseri
authors.affiliation: 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.
authors.forename: Nina
authors.initials: N
authors.lastname: Bhardwaj
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D014771:Virion / Q000276:immunology
chemical_list: D015704:CD4 Antigens