Maneglier B, Rogez-Kreuz C, Spreux-Varoquaux O, Dereuddre-Bosquet N, Martal J, Therond P, Advenier C, Dormont D, Clayette P; International Conference on AIDS (15th : 2004 : Bangkok, Thailand).
Int Conf AIDS. 2004 Jul 11-16; 15: abstract no. A10435.
Faculte de Medecine Paris Ile de France Ouest, Le Chesnay, France
Background: Ovine type I IFN-tau displays the same antiretroviral properties than human IFN-ialpha but is less toxic in vitro and in vivo. Clinical use of type I IFN is associated with severe neuropsychiatric side effects, in part linked to a stimulation of the kynurenine (Kyn) pathway. Activated macrophages and microglia are apparently the only cells capable of catabolizing tryptophan (Trp) to quinolinic acid via the Kyn pathway in the central nervous system. The rate limiting enzyme of this pathway is the indoleamine 2,3-dioxygenase (IDO). In this study, we compared the effects of human IFN-ialpha and IFN-gamma to those of ovine IFN-tau on the Kyn pathway in macrophages infected or not with HIV. Methods: Human primary macrophages treated with 100 IU/mL IFN were infected or not with HIV-1/Ba-L. Trp and Kyn concentrations in cell culture supernatants were simultaneously measured by High Performance Liquid Chromatography. In parallel, IDO mRNA expression was quantified by PCR and the (Kyn/Trp) ratio allowed an estimation of IDO activity. HIV replication was assessed in cell culture supernatants. Results: Trp levels in cell culture supernatants were undetectable after 3 days of treatment with IFN-gamma and remained low throughout the period of treatment, whether the macrophages were infected or not. In parallel, a correlated induction of the Kyn pathway was observed, with high levels of IDO mRNA expression. In contrast, the effects of type I IFN (-ialpha and -tau) were weak and transient in uninfected macrophages. The low activation of the Kyn pathway was more pronounced with IFN-ialpha than with IFN-tau. In infected and untreated macrophages, the Kyn pathway was activated by high HIV replication, but the antiretroviral properties of type I IFN prevented this stimulation. Conclusions: At antiretroviral concentrations, IFN-tau had a weaker impact than IFN-ialpha on the Kyn pathway and might be considered as a future therapy in HIV or HIV/HCV infections.
Publication Types:
Keywords:
- Acquired Immunodeficiency Syndrome
- Animals
- Dioxygenases
- HIV Infections
- HIV Seropositivity
- HIV-1
- Humans
- In Vitro
- Interferon Type II
- Interferons
- Kynurenine
- Kynurenine 3-Monooxygenase
- Macrophages
- Microglia
- Quinolinic Acid
- Sheep, Domestic
- Tryptophan
Other ID:
UI: 102276335
From Meeting Abstracts