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PMID: 15961516 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, P.H.S.

Inhibition of indoleamine 2,3-dioxygenase (IDO) enhances elimination of virus-infected macrophages in an animal model of HIV-1 encephalitis.

Blood ·Vol. 106 ·No. 7 ·2005-10-01 ·Pages 2382-90

Potula R, Poluektova L, Knipe B, Chrastil J, Heilman D, Dou H, Takikawa O, Munn DH, Gendelman HE, Persidsky Y

Abstract

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.

MeSH Terms
Animals Basal Ganglia/virology Blotting, Western Brain/enzymology,metabolism,virology CD3 Complex/biosynthesis CD8 Antigens/biosynthesis CD8-Positive T-Lymphocytes/cytology,virology Cell Separation Disease Models, Animal Encephalitis, Viral/enzymology,therapy Flow Cytometry HIV Infections/enzymology,therapy Humans Image Processing, Computer-Assisted Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors Lymphocytes/cytology Macrophages/enzymology,metabolism,virology Male Mice Mice, Inbred NOD Mice, SCID Monocytes/cytology,virology T-Lymphocytes, Cytotoxic/virology Time Factors Tryptophan/analogs & derivatives,pharmacology Up-Regulation
Chemicals
CD3 Complex CD8 Antigens Indoleamine-Pyrrole 2,3,-Dioxygenase tryptophan methyl ester Tryptophan
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Potula Raghava
Center for Neurovirology and Neurodegenerative Disorders, Department of Pharmacology/Experimental Neurosciences, University of Nebraska Medical Center, Omaha, NE 68198-5215, USA.
Poluektova Larisa
Knipe Bryan
Chrastil Jesse
Heilman David
Dou Huanyu
Takikawa Osamu
Munn David H
Gendelman Howard E
Persidsky Yuri
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
0006-4971
DOI
10.1182/blood-2005-04-1403
Published
2005-10-01
Epub
2005-00-16
Pages
2382-90
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC1895260
Subset
IM
Grants
NINDS NIH HHS · 1P01 NS043 985-01 · United States
NIMH NIH HHS · R0-1 MH65 151-01A1 · United States
External Links
PubMed source DOI: 10.1182/blood-2005-04-1403 PMC Full Text View journal details
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