title: HIV-1 Tat protein enhances the intracellular growth of Leishmania amazonensis via the ds-RNA induced protein PKR.
abstract: 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.
authors.affiliation: Laboratório de Parasitologia Molecular, Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Áislan de Carvalho
authors.initials: Áde C
authors.lastname: Vivarini
authors.affiliation: Laboratório de Parasitologia Molecular, Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Renata de Meirelles Santos
authors.initials: Rde M
authors.lastname: Pereira
authors.affiliation: Laboratório de Pesquisas sobre o Timo, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Victor
authors.initials: V
authors.lastname: Barreto-de-Souza
authors.affiliation: Laboratório de Pesquisas sobre o Timo, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Jairo Ramos
authors.initials: JR
authors.lastname: Temerozo
authors.affiliation: Laboratório de Imunobiologia de Leishmanioses, Instituto de Microbiologia Paulo Góes, Universidade Federal do Rio Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Deivid C
authors.initials: DC
authors.lastname: Soares
authors.affiliation: Laboratório de Imunobiologia de Leishmanioses, Instituto de Microbiologia Paulo Góes, Universidade Federal do Rio Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Elvira M
authors.initials: EM
authors.lastname: Saraiva
authors.affiliation: Departamento de Microbiologia, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Alessandra Mattos
authors.initials: AM
authors.lastname: Saliba
authors.affiliation: Laboratório de Pesquisas sobre o Timo, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Dumith Chequer
authors.initials: DC
authors.lastname: Bou-Habib
authors.affiliation: Laboratório de Parasitologia Molecular, Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Ulisses Gazos
authors.initials: UG
authors.lastname: Lopes
mesh_terms: D002460:Cell Line; D004789:Enzyme Activation; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D042541:Intracellular Space / Q000469:parasitology; D007891:Leishmania / Q000254:growth & development* / Q000378:metabolism; D007896:Leishmaniasis / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D008264:Macrophages / Q000201:enzymology / Q000469:parasitology; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012330:RNA, Double-Stranded / Q000378:metabolism*; D015398:Signal Transduction; D019892:eIF-2 Kinase / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D012330:RNA, Double-Stranded; D054322:tat Gene Products, Human Immunodeficiency Virus; D016753:Interleukin-10; D052247:Nitric Oxide Synthase Type II; D019892:eIF-2 Kinase