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.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Actin-Related Protein 2-3 Complex / metabolism
-
Actins / metabolism
-
Carrier Proteins / metabolism
-
Cell Surface Extensions / drug effects
-
Cell Surface Extensions / metabolism
-
Cytoskeleton / drug effects
-
Cytoskeleton / metabolism*
-
Cytoskeleton / ultrastructure
-
Dendritic Cells / drug effects
-
Dendritic Cells / ultrastructure
-
Dendritic Cells / virology*
-
Enzyme Activation / drug effects
-
Formins
-
HEK293 Cells
-
HIV Infections / metabolism
-
HIV Infections / virology
-
HIV-1 / drug effects
-
HIV-1 / metabolism*
-
HIV-1 / ultrastructure
-
Humans
-
Intercellular Signaling Peptides and Proteins / pharmacology*
-
Models, Biological
-
Nerve Tissue Proteins / metabolism
-
Nerve Tissue Proteins / pharmacology*
-
Protein Binding / drug effects
-
Proto-Oncogene Protein c-fli-1 / metabolism
-
Pseudopodia / drug effects
-
Pseudopodia / metabolism
-
Receptors, Immunologic / metabolism
-
Roundabout Proteins
-
T-Lymphocytes / drug effects
-
T-Lymphocytes / metabolism
-
T-Lymphocytes / virology*
-
Virion / metabolism
-
Virion / ultrastructure
-
Wiskott-Aldrich Syndrome Protein / metabolism
-
cdc42 GTP-Binding Protein / metabolism
-
src-Family Kinases / metabolism
Substances
-
Actin-Related Protein 2-3 Complex
-
Actins
-
Carrier Proteins
-
DIAPH2 protein, human
-
FLI1 protein, human
-
Formins
-
Intercellular Signaling Peptides and Proteins
-
Nerve Tissue Proteins
-
Proto-Oncogene Protein c-fli-1
-
Receptors, Immunologic
-
Wiskott-Aldrich Syndrome Protein
-
src-Family Kinases
-
cdc42 GTP-Binding Protein
-
Slit homolog 2 protein