HIV inhibits CD4+ T-cell proliferation by inducing indoleamine 2,3-dioxygenase in plasmacytoid dendritic cells.
Infection with the human immunodeficiency virus type-1 (HIV) results in acute and progressive numeric loss of CD4(+) T-helper cells and functional impairment of T-cell responses. The mechanistic basis of the functional impairment of the surviving cells is not clear. Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme that inhibits T-cell proliferation by catabolizing the essential amino acid tryptophan (Trp) into the kynurenine (kyn) pathway. Here, we show that IDO mRNA expression is elevated in peripheral blood mononuclear cells (PBMCs) from HIV(+) patients compared with uninfected healthy controls (HCs), and that in vitro inhibition of IDO with the competitive blocker 1-methyl tryptophan (1-mT) results in increased CD4(+) T-cell proliferative response in PBMCs from HIV-infected patients. We developed an in vitro model in which exposure of PBMCs from HCs to either infectious or noninfectious, R5- or X4-tropic HIV induced IDO in plasmacytoid dendritic cells (pDCs). HIV-induced IDO was not inhibited by blocking antibodies against interferon type I or type II, which, however, induced IDO in pDCs when added to PBMC cultures. Blockade of gp120/CD4 interactions with anti-CD4 Ab inhibited HIV-mediated IDO induction. Thus, induction of IDO in pDCs by HIV may contribute to the T-cell functional impairment observed in HIV/AIDS by a non-interferon-dependent mechanism.
Boasso
Adriano
A
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20815, USA. boassoa@mail.nih.gov
Herbeuval
Jean-Philippe
JP
Hardy
Andrew W
AW
Anderson
Stephanie A
SA
Dolan
Matthew J
MJ
Fuchs
Dietmar
D
Shearer
Gene M
GM
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000821:virology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015658:HIV Infections / Q000201:enzymology / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000276:immunology*; D007372:Interferons / Q000276:immunology; D007737:Kynurenine / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008297:Male; D010950:Plasma Cells / Q000276:immunology*; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D014364:Tryptophan; D007372:Interferons