HIV-1 Tat protein enhances the intracellular growth of Leishmania amazonensis via the ds-RNA induced protein PKR

• Published in: Scientific reports Vol. 5; no. 1; p. 16777
• Main Authors: Vivarini, Áislan de Carvalho, Pereira, Renata de Meirelles Santos, Barreto-de-Souza, Victor, Temerozo, Jairo Ramos, Soares, Deivid C, Saraiva, Elvira M, Saliba, Alessandra Mattos, Bou-Habib, Dumith Chequer, Lopes, Ulisses Gazos
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 26.11.2015
• Subjects: Cell Line; eIF-2 Kinase - metabolism; Enzyme Activation; HIV-1 - metabolism; Humans; Interleukin-10 - metabolism; Intracellular Space - parasitology; Leishmania - growth & development; Leishmania - metabolism; Leishmaniasis - metabolism; Leishmaniasis - parasitology; Leishmaniasis - pathology; Macrophages - enzymology; Macrophages - parasitology; NF-kappa B - metabolism; Nitric Oxide Synthase Type II - metabolism; Protein Structure, Tertiary; RNA, Double-Stranded - metabolism; Signal Transduction; tat Gene Products, Human Immunodeficiency Virus - chemistry; tat Gene Products, Human Immunodeficiency Virus - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep16777

HIV-1 co-infection with human parasitic diseases is a growing public health problem worldwide. Leishmania parasites infect and replicate inside macrophages, thereby subverting host signaling pathways, including the response mediated by PKR. The HIV-1 Tat protein interacts with PKR and plays a pivotal role in HIV-1 replication. This study shows that Tat increases both the expression and activation of PKR in Leishmania-infected macrophages. Importantly, the positive effect of Tat addition on parasite growth was dependent on PKR signaling, as demonstrated in PKR-deficient macrophages or macrophages treated with the PKR inhibitor. The effect of HIV-1 Tat on parasite growth was prevented when the supernatant of HIV-1-infected macrophages was treated with neutralizing anti-HIV-1 Tat prior to Leishmania infection. The addition of HIV-1 Tat to Leishmania-infected macrophages led to inhibition of iNOS expression, modulation of NF-kB activation and enhancement of IL-10 expression. Accordingly, the expression of a Tat construct containing mutations in the basic region (49-57aa), which is responsible for the interaction with PKR, favored neither parasite growth nor IL-10 expression in infected macrophages. In summary, we show that Tat enhances Leishmania growth through PKR signaling.