期刊
JOURNAL OF INFECTIOUS DISEASES
卷 210, 期 3, 页码 383-391出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jiu115
关键词
Tryptophan; kynurenine; indoleamine 2,3-dioxygenase-1; HIV; mortality; antiretroviral therapy; Uganda
资金
- National Institutes of Health [R56AI100765, R21AI078774, K24MH087227, K23MH087228, T32AA007240, R01MH054907, P30AI27763, U19 AI96109, D43 CA153717, P01 AI076174]
- Doris Duke Charitable Foundation [2008047]
- Sullivan Family Foundation
Background. Human immunodeficiency virus (HIV) infection-induced indoleamine 2,3-dioxygenase-1 (IDO) expression in activated monocytes and dendritic cells catabolizes tryptophan to kynurenine and other downstream catabolites that inhibit T-cell proliferation and interleukin 17 (IL-17) production. The prognostic significance of this pathway in treated HIV disease is unknown. Methods. We measured systemic IDO activity (calculated as the ratio of plasma levels of kynurenine to tryptophan; hereafter, the KT ratio) in HIV-infected Ugandans before and during antiretroviral therapy (ART)-mediated viral suppression and its association with the rate of subsequent CD4(+) T-cell count recovery and mortality. Results. Among 435 participants, a higher pre-ART KT ratio was associated with a higher plasma virus load (P < .001) and lipopolysaccharide level (P = .018), a lower CD4(+) T-cell count (P < .001), and female sex (P = .047). Through month 12 of ART-mediated viral suppression, the plasma KT ratio decreased by approximately 50% (P < .001). After adjustment for pre-ART CD4(+) T-cell count, virus load, age, and sex, a higher month 12 KT ratio predicted a slower rate of subsequent CD4(+) T-cell count recovery (P = .001). Thirty-nine participants died. After adjustment for pre-ART CD4(+) T-cell count, virus load, body mass index, sex, and age, a higher pre-ART and month 6 KT ratio predicted increased mortality (P <= .016). Conclusions. The kynurenine pathway of tryptophan catabolism independently predicts poor CD4(+) T-cell count recovery and increased mortality among HIV-infected Ugandans initiating ART and may be an important target for interventions.
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