Abstract
Abstract 3225▪▪This icon denotes a clinically relevant abstractDissemination 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. Disclosures:No relevant conflicts of interest to declare.
Highlights
HIV becomes established at mucosal sites by infecting dendritic cells, CD4+ T lymphocytes and macrophages in the lamina propria after its entry
Virus and virus-infected cells move through lymphatic endothelial channels to draining lymph nodes where they infect various cells, including their major target cells, CD4+ T lymphocytes
We demonstrated that in lymphatic endothelium the interactions among Robo4, Slit2, fibronectin and a5b1 integrin modulate the effect of HIV-1 gp120 on lymphatic permeability
Summary
HIV becomes established at mucosal sites by infecting dendritic cells, CD4+ T lymphocytes and macrophages in the lamina propria after its entry. Virus and infected cells disseminate via lymphatic endothelial channels to the draining lymph nodes, and subsequently pass into the bloodstream [1,2,3,4]. While HIV can infect endothelial cells, its biological importance in the pathogenesis of AIDS is unclear [8,9,10]. Current knowledge of the effects of HIV-associated hyperpermeability are limited to disrupting the integrity of vascular structures and/or enhancing inflammatory reactions. These phenomena are characteristic of many infectious diseases [15] and do not explain the unique biology of HIV. While a pivotal role for the lymphatic system in the pathogenesis of HIV/AIDS has been suggested [16], the pathobiology of HIV interaction with lymphatic endothelium has not been extensively characterized
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