5,7-Dihydroxy-6-Methoxy-Flavonoids Eliminate HIV-1 D3-transfected Cytoprotective Macrophages by Inhibiting the PI3K/Akt Signaling Pathway.

Flavonoids, well-documented secondary metabolites in many vegetables and plants, exhibit antiinflammatory, anti-oxidant, anti-microbial, and anticancer activities. However, their cytotoxic effects against human immunodeficiency virus type 1 (HIV-1)-infected cytoprotective macrophages have not been studied. In the present study, we investigated their effects and their molecular mechanisms. Treatment with flavonoids in the presence of lipopolysaccharide (LPS)/cycloheximide (CHX) potently eliminated HIV-1 Tat-transduced cytoprotective human microglial CHME5 cells; the 5,7-dihydroxy-6-methoxy-flavonoids oroxylin A and tectorigenin, at a concentration of 10 μM, most potently eliminated the cytoprotective phenotype. These flavonoids eliminated Tat-transduced CHME5 cells, D3-transfected CHME5 cells, and HIV-1 D3-infected human primary macrophages, in a dose-dependent manner. Furthermore, oroxylin A and tectorigenin potently inhibited LPS/CHX-induced phosphorylation of phosphoinositide 3-kinase (PI3K), pyruvate dehydrogenase lipoamide kinase isozyme 1, Akt, and glycogen synthase kinase-3β in the Tat-transduced cells, D3-transfected CHME5 cells, and D3-infected human primary macrophages. Based on these findings, 5,7-dihydroxy-6-methoxy-flavonoids may eliminate HIV-1 infected cytoprotective macrophages by inhibiting the PI3K/Akt signaling pathway and deliver anti-HIV-1 effects in vivo by shortening the lifespan of infected macrophages.