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* Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Immunology Department, Imperial College, Chelsea and Westminster Hospital, London, U.K.;
Animal Models and Retroviral Vaccines Section, National Cancer Institute, National Institutes of Health, Bethesda MD 20892; and
Division of Biological Chemistry Biocentre, Innsbruck Medical University, Innsbruck, Austria
Increased activity of IDO, which catalyzes the degradation of Trp into kynurenine (Kyn), is observed during HIV/SIV infection, and it may contribute to the persistence of HIV/SIV by suppressing antiviral T cell responses. We administered the IDO inhibitor 1-methyl-D-tryptophan (D-1mT) for 13 days to SIV-infected rhesus macaques receiving antiretroviral therapy (ART). D-1mT treatment increased the plasma levels of Trp, without reducing the levels of Kyn, suggesting only a partial effect on IDO enzymatic activity. Surprisingly, D-1mT significantly reduced the virus levels in plasma and lymph nodes of ART-treated animals with incomplete responsiveness to ART. In SIV-infected animals that were not receiving ART, D-1mT was ineffective in reducing the plasma viral load and had only a marginal effect on the plasma Kyn/Trp ratio. Increased IDO and TGF-β mRNA expression in lymph nodes of ART-treated macaques after D-1mT treatment suggested that compensatory counterregulatory mechanisms were activated by D-1mT, which may account for the lack of effect on plasma Kyn. Finally, D-1mT did not interfere with the ART-induced T cell dynamics in lymph nodes (increased frequency of total CD4 T cells, increase of CD8 T cells expressing the antiapoptotic molecule Bcl2, and reduction of regulatory T cells). Thus, D-1mT appeared to synergize with ART in inhibiting viral replication and did not interfere with the beneficial immunologic effects of ART. Further studies are required to elucidate the immunologic or virologic mechanism by which D-1mT inhibited SIV replication in vivo.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (to A.B., M.V., A.W.D., W.P.T., E.T., G.M.S., and G.F.), and by the government of the State of the Austrian Tyrol (to D.F.).
2 A.B. and M.V. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Adriano Boasso, Imperial College, Faculty of Medicine, Department of Immunology, Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, U.K. E-mail address: a.boasso{at}imperial.ac.uk
4 Current address: Vitae Pharmaceuticals, Ft. Washington, PA 19034.
5 Current address: Department of Microbiology Diagnostics, Medical University of Bialystok, Bialystok, Poland.
6 Abbreviations used in this paper: ART, antiretroviral therapy; D-1mT, 1-methyl-D-tryptophan; Kyn, kynurenine; Neo, neopterin; Treg, regulatory T cell.
7 The online version of this article contains supplemental material.
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