IncreasedLeishmaniaReplication in HIV‐1–Infected Macrophages Is Mediated by Tat Protein through Cyclooxygenase‐2 Expression and Prostaglandin E₂Synthesis

Abstract

Protozoan parasites of the genus Leishmania frequently occur as opportunistic pathogens in human immunodeficiency virus type 1 (HIV-1)-infected individuals, but the mechanisms underlying protozoan growth in this context are poorly understood. Here, we demonstrate that the HIV-1 Tat protein drives Leishmania replication in primary human macrophages. We found that Leishmania growth doubled in HIV-1-infected macrophages and that anti-Tat antibodies reduced the exacerbated protozoan replication by 70%. Recombinant Tat increased Leishmania replication and overrode the leishmanicidal effect induced by interferon-gamma , allowing Leishmania replication even in the presence of this cytokine. Tat induced cyclooxygenase (COX)-2 expression and prostaglandin E2 (PGE2) synthesis, and a COX-2 inhibitor abolished the Tat-mediated augmentation of Leishmania replication. Moreover, PGE2 increased Leishmania growth, which was abrogated by anti-transforming growth factor (TGF)- beta1 monoclonal antibodies. Neutralization of TGF-beta1 reduced parasite growth in Leishmania-infected macrophages exposed to Tat by 50%. Our findings suggest that Tat generates a milieu permissive to Leishmania growth in individuals infected with HIV-1.

HIV/AIDS-associated visceral leishmaniasis in patients from an endemic area in Central-west Brazil

“…Overall, these data reinforced the idea that HIV/AIDS can be a predisposing condition for VL (Cacopardo et al. 1996, Wolday et al 1999, Barreto-de-Souza et al 2006, Alvar et al 2008) and the hypothesis that VL can be a predisposing condition for HIV/AIDS progression should also be considered. Therefore, improving the epidemiological surveillance of HIV infection among VL patients may lead to a precocious diagnosis before the onset of severe immunodeficiency.…”

The Relationship between Leishmaniasis and AIDS: the Second 10 Years

“…Barreto-de-Souza et al (25) recently studied the role of the transcriptional transactivator (Tat) protein, an essential viral gene product for HIV-1 replication, in the exacerbation of Leishmania proliferation in human macrophages. Tat is secreted in large amounts by cells infected by HIV-1 and is able to stimulate secretion of IL-1␤, IL-4, IL-6, IL-8, transforming growth factor beta (TGF-␤), TNF-␣, and TNF-␤.…”

American Tegumentary Leishmaniasis and HIV-AIDS Association in a Tertiary Care Center in the Brazilian Amazon

“…7,11 Leishmaniasis resolution requires an effective cellular immune response, and because immune function is particularly affected by HIV infection, it is not surprising that modifications in ATL presentation and response to treatment have been described. 7,12,13 The majority of reports of ATL/HIV-AIDS association have originated from areas of Latin America where L. ( V. ) braziliensis is the major causative parasite. It has been shown that the disease caused by L. ( V. ) braziliensis and L. ( V. ) guyanensis differs regarding clinical and therapeutic aspects.…”