Increased Leishmania replication in HIV-1-infected macrophages is mediated by tat protein through cyclooxygenase-2 expression and prostaglandin E2 synthesis.
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.
Barreto-de-Souza
Victor
V
Laboratorio de Imunologia Clinica, Departamento de Imunologia, Rio de Janeiro, RJ, Brazil.
Pacheco
Graziela J
GJ
Silva
Adriana R
AR
Castro-Faria-Neto
Hugo C
HC
Bozza
Patricia T
PT
Saraiva
Elvira M
EM
Bou-Habib
Dumith Chequer
DC
D000818:Animals; D000914:Antibodies, Viral / Q000378:metabolism; D000068579:Celecoxib; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000032:analysis / Q000096:biosynthesis; D015696:Gene Products, tat / Q000502:physiology*; D015658:HIV Infections / Q000150:complications*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007891:Leishmania / Q000254:growth & development* / Q000502:physiology; D007896:Leishmaniasis / Q000150:complications*; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology* / Q000821:virology; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000502:physiology; D054322:tat Gene Products, Human Immunodeficiency Virus
D000914:Antibodies, Viral; D016861:Cyclooxygenase Inhibitors; D015696:Gene Products, tat; D011720:Pyrazoles; D013449:Sulfonamides; D016212:Transforming Growth Factor beta; D054322:tat Gene Products, Human Immunodeficiency Virus; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone