title: Slit2N Inhibits Transmission of HIV-1 from Dendritic Cells to T-cells by Modulating Novel Cytoskeletal Elements.
abstract: Dendritic cells are among the first cells to encounter sexually acquired human immunodeficiency virus (HIV-1), in the mucosa, and they can transmit HIV-1 to CD4(+) T-cells via an infectious synapse. Recent studies reveal that actin-rich membrane extensions establish direct contact between cells at this synapse and facilitate virus transmission. Genesis of these contacts involves signaling through c-Src and Cdc42, which modulate actin polymerization and filopodia formation via the Arp2/3 complex and Diaphanous 2 (Diaph2). We found that Slit2N, a ligand for the Roundabout (Robo) receptors, blocked HIV-1-induced signaling through Arp2/3 and Diaph2, decreased filopodial extensions on dendritic cells, and inhibited cell-to-cell transmission of HIV-1 in a Robo1-dependent manner. Employing proteomic analysis, we identified Flightless-1 as a novel, Robo1-interacting protein. Treatment with shRNAs reduced levels of Flightless-1 and demonstrated its role in efficient cell-to-cell transfer of HIV-1. These results suggest a novel strategy to limit viral infection in the host by targeting the Slit/Robo pathway with modulation of cytoskeletal elements previously unrecognized in HIV-1 transmission.
authors.affiliation: Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Shrivastava
authors.affiliation: Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Prasad
authors.affiliation: Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.|DynaMed, EBSCO Information Services, 10 Estes Street, Ipswich, Massachusetts, USA.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Kuzontkoski
authors.affiliation: Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Yu
authors.affiliation: Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jerome E
authors.initials: JE
authors.lastname: Groopman
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D022081:Cell Surface Extensions / Q000187:drug effects / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D003713:Dendritic Cells / Q000187:drug effects / Q000648:ultrastructure / Q000821:virology*; D004789:Enzyme Activation / Q000187:drug effects; D000080865:Formins; D057809:HEK293 Cells; D015658:HIV Infections / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D051789:Proto-Oncogene Protein c-fli-1 / Q000378:metabolism; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D014771:Virion / Q000378:metabolism / Q000648:ultrastructure; D051316:Wiskott-Aldrich Syndrome Protein / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D002352:Carrier Proteins; D000080865:Formins; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D051789:Proto-Oncogene Protein c-fli-1; D011971:Receptors, Immunologic; D051316:Wiskott-Aldrich Syndrome Protein; D020764:cdc42 GTP-Binding Protein; D019061:src-Family Kinases; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C491462:DIAPH2 protein, human; C078433:FLI1 protein, human