Down‐regulation of LFA‐1‐mediated T cell adhesion induced by the HIV envelope glycoprotein gp160 requires phosphatidylinositol‐3‐kinase activity

Abstract

Human immunodeficiency virus binds to CD4+ T lymphocyte by the interaction, in part, between its gp120 envelope glycoprotein and the CD4 molecule. We and others have reported that the lipid kinase phosphatidylinositol-3-kinase (PI3-kinase) is associated with the CD4-p56lck complex and can be activated by various CD4 ligands. In a previous report we showed that the gp160 envelope down-regulates lymphocyte function-associated antigen-1 (LFA-1)-dependent adhesion between CD4+ T cells and B cells. This down-regulation was shown to be p56lck-dependent. Here we investigate the role of PI3-kinase in the inhibition of adhesion induced by gp160 binding to CD4. We found that gp160 activates the PI3-kinase of HUT78 CD4+ T cell lines in a way dependent on CD4-p56lck association, since no activation was detected when the interaction between CD4 and p56lck was disrupted. It was also shown, using different inhibitors of the PI3-kinase (wortmannin, Ly294002 and antisense oligonucleotides), that this lipid kinase was necessary for the down-regulation of LFA-1-mediated adhesion induced by gp160. These results strongly suggest that PI3-kinase activation induced by gp160 leads to down-regulation of LFA-1-mediated T cell adhesion to B cells. Inhibition by gp160 of cytoskeleton rearrangement-dependent, anti-CD3-mediated T cell adhesion to B cells was blocked by neutralization of PI3-kinase activity, while inhibition of cytoskeleton rearrangement-independent, Mg(2+)-induced T cell adhesion was not. These results emphasize the role of PI3-kinase in the regulation of cytoskeleton structure. It is proposed that gp160 activates both p56lck and PI3-kinase which lead to a cytoskeleton organization unfavorable for LFA-1 function.

HIV-1 gp120-induced TNF-α production by primary human macrophages is mediated by phosphatidylinositol-3 (PI-3) kinase and mitogen-activated protein (MAP) kinase pathways

“…Recently, Francois and Klotman [42] reported that gp120 induced PI-3K activation in primary macrophages and that it was necessary for viral replication. Others have shown that PI-3K activation by HIV-1 Env, Nef, or Tat is necessary for optimal viral replication, MHC class I down-regulation, and regulation of apoptosis in infected cells [43][44][45][46][47]. In contrast, we sought to investigate the effects of gp120 apart from viral infection, as cells may be exposed to Env on noninfectious virions or shed from virus or infected cells, and evidence in vivo suggests that uninfected macrophages, as well as infected cells, are activated and produce proinflammatory cytokines.…”

Molecular Events Associated with CD4-mediated Down-regulation of LFA-1-dependent Adhesion

“…This enzyme phosphorylates the D-3 position of the inositol ring of phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PI 4-P), and phosphatidylinositol 4,5-bisphosphate (PI 4,5-P 2 ) (7). These phospholipids are one of the intermediary messengers for the CD4-mediated down-regulation of LFA-1-dependent adhesion since inhibitors of PI3-kinase activity abrogate the regulatory event (8). The mechanism by which PI3-kinase upon CD4 ligand binding mediates down-regulation of LFA-1 adhesion is unknown.…”

IMPDHII Protein Inhibits Toll-like Receptor 2-mediated Activation of NF-κB

“…Several reports indicate that SHP1 regulates the phosphorylation of p85␣ (27,29). We first confirmed that SHP1 regulates phosphorylation of p85␣ by comparing the patterns of p85␣ phosphorylation in HEK293-T2 cells transfected with wild type SHP1 or with empty vector.…”