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

Raghava Potula, Larisa Poluektova, Bryan Knipe, Jesse Chrastil, David Heilman, Huanyu Dou, Osamu Takikawa, David H Munn, Howard E. Gendelman, Yuri Persidsky

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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- γ+ T cells, and HIV-1gag/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.

Original languageEnglish (US)
Pages (from-to)2382-2390
Number of pages9
JournalBlood
Volume106
Issue number7
DOIs
StatePublished - Oct 1 2005

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Macrophages
Encephalitis
Viruses
HIV-1
Animals
Animal Models
T-cells
Tryptophan
Brain
Cytotoxic T-Lymphocytes
Lymphocytes
Blood
HIV
Quinolinic Acid
Kynurenine
T-Lymphocytes
Injections
SCID Mice
Immunosuppressive Agents

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Potula, R., Poluektova, L., Knipe, B., Chrastil, J., Heilman, D., Dou, H., ... Persidsky, Y. (2005). Inhibition of indoleamine 2,3-dioxygenase (IDO) enhances elimination of virus-infected macrophages in an animal model of HIV-1 encephalitis. Blood, 106(7), 2382-2390. https://doi.org/10.1182/blood-2005-04-1403

Inhibition of indoleamine 2,3-dioxygenase (IDO) enhances elimination of virus-infected macrophages in an animal model of HIV-1 encephalitis. / Potula, Raghava; Poluektova, Larisa; Knipe, Bryan; Chrastil, Jesse; Heilman, David; Dou, Huanyu; Takikawa, Osamu; Munn, David H; Gendelman, Howard E.; Persidsky, Yuri.

In: Blood, Vol. 106, No. 7, 01.10.2005, p. 2382-2390.

Research output: Contribution to journalArticle

Potula, R, Poluektova, L, Knipe, B, Chrastil, J, Heilman, D, Dou, H, Takikawa, O, Munn, DH, Gendelman, HE & Persidsky, Y 2005, '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, pp. 2382-2390. https://doi.org/10.1182/blood-2005-04-1403
Potula, Raghava ; Poluektova, Larisa ; Knipe, Bryan ; Chrastil, Jesse ; Heilman, David ; Dou, Huanyu ; Takikawa, Osamu ; Munn, David H ; Gendelman, Howard E. ; Persidsky, Yuri. / Inhibition of indoleamine 2,3-dioxygenase (IDO) enhances elimination of virus-infected macrophages in an animal model of HIV-1 encephalitis. In: Blood. 2005 ; Vol. 106, No. 7. pp. 2382-2390.
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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- γ+ T cells, and HIV-1gag/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.",
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AU - Dou, Huanyu

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