title: Spatiotemporal trafficking of HIV in human plasmacytoid dendritic cells defines a persistently IFN-α-producing and partially matured phenotype.
abstract: Plasmacytoid DCs (pDCs) are innate immune cells that are specialized to produce IFN-α and to activate adaptive immune responses. Although IFN-α inhibits HIV-1 replication in vitro, the production of IFN-α by HIV-activated pDCs in vivo may contribute more to HIV pathogenesis than to protection. We have now shown that HIV-stimulated human pDCs allow for persistent IFN-α production upon repeated stimulation, express low levels of maturation molecules, and stimulate weak T cell responses. Persistent IFN-α production by HIV-stimulated pDCs correlated with increased levels of IRF7 and was dependent upon the autocrine IFN-α/β receptor feedback loop. Because it has been shown that early endosomal trafficking of TLR9 agonists causes strong activation of the IFN-α pathway but weak activation of the NF-κB pathway, we sought to investigate whether early endosomal trafficking of HIV, a TLR7 agonist, leads to the IFN-α-producing phenotype we observed. We demonstrated that HIV preferentially traffics to the early endosome in human pDCs and therefore skews pDCs toward a partially matured, persistently IFN-α-secreting phenotype.
authors.affiliation: Division of Infectious Diseases, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Meagan
authors.initials: M
authors.lastname: O'Brien
authors.forename: Olivier
authors.initials: O
authors.lastname: Manches
authors.forename: Rachel Lubong
authors.initials: RL
authors.lastname: Sabado
authors.forename: Sonia Jimenez
authors.initials: SJ
authors.lastname: Baranda
authors.forename: Yaming
authors.initials: Y
authors.lastname: Wang
authors.forename: Isabelle
authors.initials: I
authors.lastname: Marie
authors.forename: Linda
authors.initials: L
authors.lastname: Rolnitzky
authors.forename: Martin
authors.initials: M
authors.lastname: Markowitz
authors.forename: David M
authors.initials: DM
authors.lastname: Margolis
authors.forename: David
authors.initials: D
authors.lastname: Levy
authors.forename: Nina
authors.initials: N
authors.lastname: Bhardwaj
mesh_terms: D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000821:virology*; D006678:HIV / Q000378:metabolism*; D015658:HIV Infections / Q000378:metabolism*; D006801:Humans; D007107:Immune System; D016898:Interferon-alpha / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D013997:Time Factors; D051217:Toll-Like Receptor 9 / Q000819:agonists*
chemical_list: D016207:Cytokines; D016898:Interferon-alpha; D016328:NF-kappa B; D012333:RNA, Messenger; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051217:Toll-Like Receptor 9