Slit2/Robo4 Signaling Modulates HIV-1 gp120-Induced Lymphatic Hyperpermeability

PLoS Pathogens

Dean Y. Li¹  Weiquan Zhu¹  Jinlong Yu²  Xuefeng Zhang²  Paula M. Kuzontkoski²  Jerome E. Groopman² 

[1] Department of Medicine and Molecular Medicine Program, University of Utah, Salt Lake City, Utah, United States of America;Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America

关键词: HIV-1;    Permeability;    Integrins;    Vascular permeability;    Endothelial cells;    HIV;    Immunoprecipitation;    Endothelium;   

DOI  :  10.1371/journal.ppat.1002461

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY