Increased Leishmania Replication in HIV-1–Infected Macrophages Is Mediated by Tat Protein through Cyclooxygenase-2 Expression

Protozoan parasites of the genus Leishmania frequently occur as opportunistic pathogens in human immu-nodeficiency 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-g, 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–trans-forming growth factor (TGF)–b1 monoclonal antibodies. Neutralization of TGF-b1 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. Macrophages are productively infected by HIV-1, the etiological agent (along with HIV-2) of AIDS. These cells appear to be resistant to the cytopathic effect o