Inhibition of indoleamine 2,3-dioxygenase (IDO) enhances elimination of virus-infected macrophages in an animal model of HIV-1 encephalitis.
Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme in the kynurenine pathway of tryptophan metabolism. IDO activity is linked with immunosuppression by its ability to inhibit lymphocyte proliferation, and with neurotoxicity through the generation of quinolinic acid and other toxins. IDO is induced in macrophages by HIV-1 infection, and it is up regulated in macrophages in human brain tissue with HIV-1 encephalitis (HIVE). Using a model of HIVE, we investigated whether IDO inhibitor 1-methyl-d-tryptophan (1-MT) could affect the generation of cytotoxic T lymphocytes (CTLs) and clearance of virus-infected macrophages from the brain. Severe combined immunodeficient mice were reconstituted with human peripheral blood lymphocytes, and encephalitis was induced by intracranial injection of autologous HIV-1-infected monocyte-derived macrophages (MDMs). Animals treated with 1-MT demonstrated increased numbers of human CD3+, CD8+, CD8+/interferon-gamma+ T cells, and HIV-1(gag/pol)-specific CTLs in peripheral blood compared with controls. At week 2 after MDM injection in the basal ganglia, mice treated with 1-MT showed a 2-fold increase in CD8+ T lymphocytes in the areas of the brain containing HIV-1-infected MDMs compared with untreated controls. By week 3, 1-MT-treated mice showed 89% reduction in HIV-infected MDMs in brain as compared with controls. Thus, manipulation of immunosuppressive IDO activity in HIVE may enhance the generation of HIV-1-specific CTLs, leading to elimination of HIV-1-infected macrophages in brain.
Potula
Raghava
R
Center for Neurovirology and Neurodegenerative Disorders, Department of Pharmacology/Experimental Neurosciences, University of Nebraska Medical Center, Omaha, NE 68198-5215, USA.
Poluektova
Larisa
L
Knipe
Bryan
B
Chrastil
Jesse
J
Heilman
David
D
Dou
Huanyu
H
Takikawa
Osamu
O
Munn
David H
DH
Gendelman
Howard E
HE
Persidsky
Yuri
Y
D000818:Animals; D001479:Basal Ganglia / Q000821:virology; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology / Q000378:metabolism / Q000821:virology; D017252:CD3 Complex / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000821:virology; D002469:Cell Separation; D004195:Disease Models, Animal; D018792:Encephalitis, Viral / Q000201:enzymology / Q000628:therapy*; D005434:Flow Cytometry; D015658:HIV Infections / Q000201:enzymology / Q000628:therapy*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors*; D008214:Lymphocytes / Q000166:cytology; D008264:Macrophages / Q000201:enzymology* / Q000378:metabolism / Q000821:virology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009000:Monocytes / Q000166:cytology / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000821:virology; D013997:Time Factors; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology; D015854:Up-Regulation
D017252:CD3 Complex; D016827:CD8 Antigens; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C028129:tryptophan methyl ester; D014364:Tryptophan