12th Conference on Retroviruses and Opportunistic Infections Boston, Massachusetts - February 22-25, 2005

Conf Retrovir Opportunistic Infect 2005 Feb 22-25;12:abstract no. 14

Raghava Potula¹, L Poluektova¹, B Knipe¹, J Chrastil¹, D Heilman¹, H Dou¹, H Gendelman¹, D Munn², and Y Persidisky^1
1Univ of Nebraska Med Ctr, Omaha, USA and ²Med Coll of Georgia, Augusta

BACKGROUND: Failure to eliminate HIV-1-infected macrophages by cytotoxic lymphocytes (CTL) in the brain may be due to presentation of HIV antigen by tolerogenic antigen presenting cells (like macrophages). A rate limiting enzyme of kynurenine pathway of tryptophan metabolism, indoleamine 2,3-dioxygenase (IDO) is up-regulated in virus-infected macrophages and is implicated in the inhibition of antigen-specific T-cell proliferation. IDO also plays a key role in neurotoxin production (quinolinic acid and others) leading to HIV-associated dementia. We hypothesized that IDO inhibition may enhance generation of HIV-specific CTL and promote clearance of virus from the “immunological reservoir” formed by brain macrophages.

METHODS: A previously established SCID mouse model of human HIV-1 encephalitis (HIVE) was used in our experiments. Non-obese SCID mice were reconstituted with human peripheral blood lymphocytes, and focal encephalitis was induced by stereotactic intracranial injection of autologous HIV-1-infected monocyte-derived macrophages (MDM). Animals were treated subcutaneously with IDO inhibitor, 1-methyl-D-tryptophan (1-MT) or placebo. FACS analysis (CD3/CD8/CD4/IFN-γ) was performed on peripheral blood (week 1 to 3) and spleen (week 2 and 3). Animals were sacrificed on week 2 and 3 post-MDM inoculation. The number of human CD8+ lymphocytes, virus-infected MDM, human IDO expression, and mouse neuro-inflammatory responses were determined by quantitative immunohistochemistry in the brain. Statistical analysis was performed using one-way analysis of variance. A value of p < 0.05 was considered statistically significant.

RESULTS: Equal numbers of lymphocytes were found in the spleen of placebo and 1-MT mice by FACS analysis indicating similar levels of engraftment. One week following MDM injection 1-MT-treated mice demonstrated increased human CD3+, CD8+, and IFN-γ producing lymphocytes in peripheral blood as compared to placebo group. At week 2, 1-MT-treated mice showed 2-fold increase in CD8+ T lymphocytes in the areas containing HIV-1 MDM in brain, while a similar number of HIV-1 MDM were seen in the brains of both groups. By week 3, 1-MT-treated mice showed significant reduction of HIV-1-infected MDM as compared with placebo group (3.33 vs 30.25 MDM per section, p < 0.05).

CONCLUSIONS: These results indicate that IDO inhibition leads to effective elimination of HIV-1-infected MDM in the brain offering new strategies for therapeutic intervention in HIVE.

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