Increased Leishmania replication in HIV-1-infected macrophages is mediated by tat protein through cyclooxygenase-2 expression and prostaglandin E2 synthesis

J Infect Dis. 2006 Sep 15;194(6):846-54. doi: 10.1086/506618. Epub 2006 Aug 10.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Viral / metabolism
  • Celecoxib
  • Cells, Cultured
  • Cyclooxygenase 2 / biosynthesis
  • Cyclooxygenase Inhibitors / pharmacology
  • Dinoprostone / analysis
  • Dinoprostone / biosynthesis
  • Gene Products, tat / physiology*
  • HIV Infections / complications*
  • HIV-1 / physiology*
  • Humans
  • Leishmania / growth & development*
  • Leishmania / physiology
  • Leishmaniasis / complications*
  • Macrophages / drug effects
  • Macrophages / parasitology*
  • Macrophages / virology
  • Pyrazoles / pharmacology
  • Sulfonamides / pharmacology
  • Transforming Growth Factor beta / physiology
  • tat Gene Products, Human Immunodeficiency Virus


  • Antibodies, Viral
  • Cyclooxygenase Inhibitors
  • Gene Products, tat
  • Pyrazoles
  • Sulfonamides
  • Transforming Growth Factor beta
  • tat Gene Products, Human Immunodeficiency Virus
  • Cyclooxygenase 2
  • Celecoxib
  • Dinoprostone