Shrivastava, AshutoshPrasad, AnilKuzontkoski, Paula M.Yu, JinlongGroopman, Jerome2015-12-042015Shrivastava, Ashutosh, Anil Prasad, Paula M. Kuzontkoski, Jinlong Yu, and Jerome E. Groopman. 2015. “Slit2N Inhibits Transmission of HIV-1 from Dendritic Cells to T-cells by Modulating Novel Cytoskeletal Elements.” Scientific Reports 5 (1): 16833. doi:10.1038/srep16833. http://dx.doi.org/10.1038/srep16833.2045-2322http://nrs.harvard.edu/urn-3:HUL.InstRepos:23845153Dendritic 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.en-USJournal Article2015-12-0410.1038/srep16833