Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy

Abstract

Since HIV-1 infected macrophages display highly elevated Akt activity, our results collectively show that PI3K/Akt inhibitors may be a novel therapy for interfering with the establishment of long-living HIV-1 infected reservoirs.

Ginsenoside Rh1 Eliminates the Cytoprotective Phenotype of Human Immunodeficiency Virus Type 1-Transduced Human Macrophages by Inhibiting the Phosphorylation of Pyruvate Dehydrogenase Lipoamide Kinase Isozyme 1

“…Therefore, PI3K/Akt phosphorylation inhibitors could serve not only as effective anticancer drugs but also as anti-viral agents. 3,20) In this study, we found that ginsenoside Rh1 inhibits the Tat-induced PI3K/ Akt cell survival pathway, thereby leading to the death of HIV-1-expressing macrophages and CHME5 cells, similar to previously reported findings using compound K. 17) However, ginsenoside Rh1 inhibited PDK1 phosphorylation in the PI3K/ Akt signaling pathway, whereas compound K did not. Furthermore, ginsenoside Rh1 also abolished the cytoprotective D3-infected human primary macrophages, as well as the PDK1/ Akt pathway.…”

“…4). Miltefosine abolishes the cytoprotective effect of HIV-1 infected macrophages by inhibiting the PI3K/Akt pathway, 3) but it exhibits severe side effects, such as nausea, vomiting and teratotoxicity. 19) To reduce the required dose of miltefosine, we investigated the combined effect of miltefosine and ginsenoside Rh1 against Tat-transduced CHME5 cells.…”

“…1,2) HIV-1 infection activates the PI3K/Akt cell survival pathway in primary human macrophages and renders these cells resistant to cytotoxic insults. 2,3) Expression of the Tat protein, which is an HIV-1 antigen, elevates the cytoprotective phenotype of the human microglial cell line CHME5 as well as human primary macrophages. Tat-expressing CHME5 cells proactively activate the PI3K/Akt pathway upon exposure to cellular stresses by reducing the levels of phosphate and tensin homology, which is a negative regulator of the Akt pathway.…”

“…6,7) Therefore, many studies have attempted to use chemicals to control the cytoprotective effects of HIV-1-infected macrophages. 1,3) Red ginseng (the steamed root of Panax ginseng C.A. Meyer, Araliaceae), which contains protopanaxadiol and protopanaxatriol ginsenosides as its main constituents, is frequently used to treat tumor, diabetes, inflammation, stress and acquired immunodeficiency syndrome (AIDS) in Asian countries.…”

Clionosterol and Ethyl Cholestan-22-enol Isolated from the Rhizome of <i>Polygala tenuifolia</i> Inhibit Phosphatidylinositol 3-Kinase/Akt Pathway

“…Of them, the expression of Tat appears to inactivate a negative regulator of the PI3K/Akt pathway, called PTEN. 5,6) The PI3K/Akt pathway is also highly activated in many cancer cell types. 7) For example, the transfection of HIV-1 Tat into CHME5 cells, a human microglial cell line, and human primary macrophages elevates their cytoprotective phenotypes against cellular stresses.…”