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HIV activates indoleamine 2,3-dioxygenease: inhibition of T cell proliferation by tryptophan starvation

T cell immune responses of HIV+ patients are functionally impaired prior to CD4+ T cell depletion. Tryptophan (trp) degradation by indoleamine-2, 3-dyoxigenase (IDO) is an immunosuppressive system that may be important in HIV/AIDS. We show here that IDO is increased in PBMC from HIV+ patients compared to controls. Culture with the IDO-inhibitor 1-methyl tryptophan (1 mT) increased proliferation of PBMC from HIV+ patients in response to PHA or anti-CD3/CD28. Exposure of PBMC from HIV-uninfected donors to infectious or noninfectious HIV increased IDO in plasmacytoid dendritic cells (pDC). Supernatants from HIV-exposed PBMC inhibited CD4+ T cell responses to PHA or anti-CD3/CD28, and this effect was reversed by 1 mT. CD8+ T cell proliferation in response to anti-CD3/CD28, but not to PHA, was also inhibited. Analysis of cyclin mRNA expression showed that CD4+ T cell were arrested in G1, whereas CD8+ T cell were blocked in G0. HIV-induced IDO inhibited expression of CD28 mRNA in CD8+ T cells. Thus HIV directly induces IDO expression in pDC, resulting in unresponsiveness of CD4+ T cells by inhibiting progression to the S phase of the cell cycle, and blocking of CD8+ T cell costimulation through downregulation of CD28.

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Correspondence to A Boasso.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Keywords

  • Immune Response
  • Cell Proliferation
  • Cell Cycle
  • mRNA Expression
  • Dendritic Cell