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. Pseudomonas aeruginosa is a common cause of pneumonia in humans. The most virulent strains produce ExoU, which is a key effector of P. aeruginosa cytotoxicity. Upon injection into the target cell cytosol by the type III secretion system (T3SS), ExoU binds to PI(4,5)P 2 on the inner leaflet of the plasma membrane. ExoU phospholipase activity then induces a loss of plasma membrane integrity, rapidly leading to cell death. HIV-1-Tat is secreted by HIV-infected cells, leading to nanomolar concentrations of Tat in the sera of PLWH, even under antiretroviral therapy. Circulating Tat is endocytosed by uninfected cells, translocates to the cytosol, and binds to PI(4,5)P 2 at the plasma membrane. In uninfected cells only, Tat is palmitoylated, enabling Tat to become resident on PI(4,5)P 2 . Here, we found that Tat interferes with the recruitment of ExoU by PI(4,5)P 2 , thereby protecting primary human macrophages from the toxicity of exoU -positive P. aeruginosa strains. Tat nevertheless enhances the toxicity of exoU -deficient strains of P. aeruginosa toward macrophages. HIV Tat might, therefore, modulate the sensitivity of PLWH toward P. aeruginosa strains depending on whether they own the key type III effector exoU . IMPORTANCE Pseudomonas aeruginosa is a common cause of pneumonia in humans and a major nosocomial pathogen. People living with HIV (PLWH), even under antiretroviral therapy, are at risk of developing infectious diseases, such as bacterial pneumonia. The T3SS plays an important role in P. aeruginosa virulence. The T3SS can inject four effectors into the target cell cytosol, including the key effector ExoU that binds to PI(4,5)P2 on the inner leaflet of the plasma membrane. The potent phospholipase activity of ExoU rapidly induces cell death. HIV-Tat is present in the serum of PLWH. Circulating Tat enters cells and binds PI(4,5)P 2 with a very high affinity. Our results indicate that HIV-Tat interferes with the recruitment of ExoU by PI(4,5)P 2 , thereby protecting macrophages from strains of P. aeruginosa that express ExoU. Tat, nevertheless, increased macrophage sensitivity to exoU-negative strains. HIV Tat could, therefore, modulate PLWH susceptibility to P. aeruginosa .