title: Slit2/Robo4 signaling modulates HIV-1 gp120-induced lymphatic hyperpermeability.
abstract: Dissemination of HIV in the host involves transit of the virus and virus-infected cells across the lymphatic endothelium. HIV may alter lymphatic endothelial permeability to foster dissemination, but the mechanism is largely unexplored. Using a primary human lymphatic endothelial cell model, we found that HIV-1 envelope protein gp120 induced lymphatic hyperpermeability by disturbing the normal function of Robo4, a novel regulator of endothelial permeability. HIV-1 gp120 induced fibronectin expression and integrin α₅β₁ phosphorylation, which led to the complexing of these three proteins, and their subsequent interaction with Robo4 through its fibronectin type III repeats. Moreover, pretreatment with an active N-terminus fragment of Slit2, a Robo4 agonist, protected lymphatic endothelial cells from HIV-1 gp120-induced hyperpermeability by inhibiting c-Src kinase activation. Our results indicate that targeting Slit2/Robo4 signaling may protect the integrity of the lymphatic barrier and limit the dissemination of HIV in the host.
authors.affiliation: Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Zhang
authors.forename: Jinlong
authors.initials: J
authors.lastname: Yu
authors.forename: Paula M
authors.initials: PM
authors.lastname: Kuzontkoski
authors.forename: Weiquan
authors.initials: W
authors.lastname: Zhu
authors.forename: Dean Y
authors.initials: DY
authors.lastname: Li
authors.forename: Jerome E
authors.initials: JE
authors.lastname: Groopman
mesh_terms: D004729:Endothelium, Lymphatic / Q000378:metabolism*; D004789:Enzyme Activation; D016391:Genes, src; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism*; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D039081:Integrin alpha5beta1 / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010539:Permeability; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000098552:Slit Homolog 2 Protein; D000097905:Roundabout Proteins
chemical_list: D015699:HIV Envelope Protein gp120; D039081:Integrin alpha5beta1; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D000098552:Slit Homolog 2 Protein; C462951:ROBO4 protein, human; D000097905:Roundabout Proteins; C514793:gp120 protein, Human immunodeficiency virus 1