Combined effect of antiretroviral therapy and blockade of IDO in SIV-infected rhesus macaques.
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-beta 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.
Boasso
Adriano
A
Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. a.boasso@imperial.ac.uk
Vaccari
Monica
M
Fuchs
Dietmar
D
Hardy
Andrew W
AW
Tsai
Wen-Po
WP
Tryniszewska
Elzbieta
E
Shearer
Gene M
GM
Franchini
Genoveffa
G
D000818:Animals; D044966:Anti-Retroviral Agents / Q000008:administration & dosage*; D002851:Chromatography, High Pressure Liquid; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005434:Flow Cytometry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors*; D007737:Kynurenine / Q000097:blood; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D008253:Macaca mulatta; D012333:RNA, Messenger / Q000032:analysis; D012367:RNA, Viral / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000187:drug effects; D014364:Tryptophan / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D014766:Viremia / Q000188:drug therapy
D044966:Anti-Retroviral Agents; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012333:RNA, Messenger; D012367:RNA, Viral; D016212:Transforming Growth Factor beta; D007737:Kynurenine; D014364:Tryptophan