Zhang, XeufengYu, JinlongKuzontkoski, Paula MarieZhu, WeiquanLi, Dean Y.Groopman, Jerome2012-08-082012Zhang, Xuefeng, JinLong Yu, Paula M. Kuzontkoski, Weiquan Zhu, Dean Y. Li, and Jerome E. Groopman. 2012. Slit2/Robo4 signaling modulates HIV-1 gp120-induced lymphatic hyperpermeability. PLoS Pathogens 8(1): e1002461.1553-7366http://nrs.harvard.edu/urn-3:HUL.InstRepos:9369657Dissemination 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 \(\alpha_5\beta_1\) 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.en-USmedicinecardiovascularvascular biologyinfectious diseasesviral diseasesHIVJournal Article2012-08-0810.1371/journal.ppat.1002461