HIV-1 Tat protects macrophages from killing by the Exoenzyme U from Pseudomonas aeruginosa

People living with HIV (PLWH) have a higher risk of developing other diseases, such as bacterial pneumonia. While Pseudomonas aeruginosa (PAE) is a common cause of pneumonia in humans, PLWHs are infrequently infected by PAE. The reasons for this relative resistance of PLWH to PAE are not known. The most virulent PAE strains produce ExoU which is a key effector of PAE cytotoxicity. Upon injection into the target cell cytosol by the type III secretion system, ExoU binds to PI(4,5)P2 on the inner leaflet of the plasma membrane. Its phospholipase activity then induces a loss of plasma membrane integrity, rapidly leading to cell death. HIV-Tat is secreted by HIV-infected cells, leading to nanomolar concentrations of Tat in the sera of PLWH, even under antiretroviral therapy. Circulating Tat can be endocytosed by uninfected cells, translocate to the cytosol and bind to PI(4,5)P2 at the plasma membrane. In uninfected cells only, Tat is palmitoylated, enabling Tat to become resident on PI(4,5)P2. We found that Tat can interfere with the recruitment of ExoU by PI(4,5)P2, thereby protecting macrophages from PAE toxicity. HIV Tat could therefore be involved in the relative protection of PLWH against the most aggressive PAE isolates and their ExoU type III effector. Tat nevertheless enhances the toxicity of ExoU-deficient PAE strains toward macrophages. ImportancePeople living with HIV (PLWH) are at risk of developing bacterial pneumonia. A widespread cause of pneumonia is Pseudomonas aeruginosa (PAE) but, for unknown reasons, PLWHs are infrequently infected by PAE. A key effector of PAE cytotoxicity is ExoU that is injected by PAE into the target cell cytosol, then binds to PI(4,5)P2 on the inner leaflet of the plasma membrane. The potent phospholipase activity of ExoU then induces a loss of plasma membrane integrity, rapidly leading to cell death. HIV-Tat is present in the serum of PLWH. Circulating Tat is endocytosed by cells, translocates to the cytosol and bind to PI(4,5)P2 at the plasma membrane with a very high affinity. This study indicates that Tat interferes with the recruitment of ExoU by PI(4,5)P2, thereby protecting macrophages from ExoU+ PAE. HIV Tat could therefore be involved in the relative protection of PLWH against the most aggressive PAE isolates.