title: Cocaine Enhances DC to T-cell HIV-1 Transmission by Activating DC-SIGN/LARG/LSP1 Complex and Facilitating Infectious Synapse Formation.
abstract: DC-SIGN is a dendritic cell surface structure which participates in binding and transmission of HIV-1. Here, for the first time we demonstrate that cocaine induces over expression of DC-SIGN and significantly enhances virus transfer from DCs to T-cells by increasing the binding and internalization of HIV-1 in DCs. We found that cocaine activates a DC-SIGN mediated 'signalosome' complex by enhancing its association with LARG and LSP1. Further, LARG was observed to participate in DC-SIGN mediated internalization of HIV-1 in DCs. Intracellular trafficking studies of HIV-1 in cocaine treated DCs revealed increased co-localization of HIV-1 with endosomal or multi vesicular body (MVB) markers such as CD81 and VPS4 and decreased co-localization with the phagolysomal marker LAMP1; this signified altered intracellular trafficking and decreased degradation of HIV-1 in cocaine treated DCs. Furthermore, we found that cocaine induced activation of LARG which in turn activated Rho A and the focal adhesion molecules FAK, Pyk2 and paxillin. This signaling cascade enhanced the formation of an infectious synapse between DCs and T-cells. Our study provides insight into the molecular mechanisms of cocaine's contribution to key components in HIV pathogenesis and highlights novel targets for interrupting the virus life cycle in substance using hosts.
authors.affiliation: Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, 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, MA 02215, USA.
authors.forename: Rutuja
authors.initials: R
authors.lastname: Kulkarni
authors.affiliation: Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Shuxian
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Jerome E
authors.initials: JE
authors.lastname: Groopman
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities / Q000378:metabolism; D001692:Biological Transport; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D003042:Cocaine / Q000378:metabolism* / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism; D015870:Gene Expression; D015658:HIV Infections / Q000378:metabolism* / Q000635:transmission* / Q000821:virology; D015497:HIV-1 / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D054992:Immunological Synapses; D037181:Lectins, C-Type / Q000378:metabolism*; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D060225:Tetraspanin 28 / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism; D053586:Virus Internalization; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D000074183:ATPases Associated with Diverse Cellular Activities; D015815:Cell Adhesion Molecules; D003042:Cocaine; D056827:Endosomal Sorting Complexes Required for Transport; D037181:Lectins, C-Type; D051907:Lysosomal Membrane Proteins; D008840:Microfilament Proteins; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D011956:Receptors, Cell Surface; D064067:Rho Guanine Nucleotide Exchange Factors; D060225:Tetraspanin 28; D025262:Vacuolar Proton-Translocating ATPases; D020742:rhoA GTP-Binding Protein; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C577222:ARHGEF12 protein, human; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C489183:LSP1 protein, human; C490305:VPS4A protein, human