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

Áislan De Carvalho Vivarini,Alessandra Mattos Saliba,Dumith Chequer Bou-Habib,Victor Barreto-De-Souza,Jairo Ramos Temerozo,Elvira M Saraiva,Ulisses Gazos Lopes,Deivid C Soares,Renata De Meirelles Santos Pereira

doi:10.1038/srep16777

Áislan De Carvalho Vivarini, Alessandra Mattos Saliba + Show 7 more

Open Access

https://doi.org/10.1038/srep16777

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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.

Highlights

human immunodeficiency virus (HIV)-1 co-infection with human parasitic diseases is a growing public health problem worldwide
We previously demonstrated that the exogenous addition of Tat increases the infection load of intracellular Leishmania amazonensis in macrophages[21], and in the present work we investigated the role of protein kinase R (PKR) in the aggravation of Leishmania infection driven by Tat
L. amazonensis induces the expression of PKR and triggers PKR signaling in macrophages[6,10]

Summary

Introduction

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. Leishmania modulates cellular signaling pathways, including increasing the expression and activation of the double-stranded RNA (dsRNA)-activated protein kinase R (PKR)[6]. Tat interacts with and is phosphorylated by PKR16,17, whose kinase activity on Tat increases HIV-1 long terminal repeat (LTR) transcription activity, thereby up-modulating viral production[18]. We previously demonstrated that the exogenous addition of Tat increases the infection load of intracellular Leishmania amazonensis in macrophages[21], and in the present work we investigated the role of PKR in the aggravation of Leishmania infection driven by Tat. Our data implicate PKR as a key molecule bridging the effect of the HIV-1 protein on parasite infection

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