The kynurenine pathway of tryptophan catabolism, CD4+ T-cell recovery, and mortality among HIV-infected Ugandans initiating antiretroviral therapy - PubMed (original) (raw)

. 2014 Aug 1;210(3):383-91.

doi: 10.1093/infdis/jiu115. Epub 2014 Feb 28.

Yap Boum 2nd 2, Yong Huang 3, Conrad Muzoora 4, Annet Kembabazi 4, Sheri D Weiser 5, John Bennett 6, Huyen Cao 7, Jessica E Haberer 8, Steven G Deeks 5, David R Bangsberg 9, Joseph M McCune 5, Jeffrey N Martin 6, Peter W Hunt 5

Affiliations

The kynurenine pathway of tryptophan catabolism, CD4+ T-cell recovery, and mortality among HIV-infected Ugandans initiating antiretroviral therapy

Helen Byakwaga et al. J Infect Dis. 2014.

Abstract

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.

Keywords: HIV; Tryptophan; Uganda; antiretroviral therapy; indoleamine 2,3-dioxygenase-1; kynurenine; mortality.

© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

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Figures

Figure 1.

Figure 1.

Factors associated with the plasma ratio of kynurenine to tryptophan (hereafter, the “KT ratio”) before antiretroviral therapy (ART) initiation in human immunodeficiency virus (HIV)–infected Ugandans. The relationships between the pre-ART KT ratio and the CD4+ T-cell count (A), the plasma HIV RNA level (B), sex and pregnancy status (C), CD4+ T-cell activation (D), CD8+ T-cell activation (E), and plasma lipopolysaccharide (LPS) level (LPS, F) were assessed in 435 HIV-infected Ugandans. Between-group comparisons were assessed with Wilcoxon rank sum tests, and Spearman correlation coefficients were used for comparing continuous variables.

Figure 2.

Figure 2.

Impact of antiretroviral therapy (ART)–mediated viral suppression on the plasma ratio of kynurenine to tryptophan (hereafter, the “KT ratio”) in human immunodeficiency virus (HIV)–infected Ugandans. Changes in the KT ratio were assessed in HIV-infected Ugandans during the first year of confirmed ART-mediated viral suppression to <400 copies/mL (A). Boxes represent interquartile ranges, and central bars reflect median values. Error bars span the 5th and 95th percentile values. P values reflect changes from baseline levels assessed with linear mixed models. The correlation between the pre-ART KT ratio and the month 12 KT ratio was also assessed (B).

Figure 3.

Figure 3.

Relationship between the plasma ratio of kynurenine to tryptophan (hereafter, the “KT ratio”) and mortality among human immunodeficiency virus (HIV)–infected Ugandans initiating antiretroviral therapy (ART). The relationship between the KT ratio measured before ART initiation (A) and at month 6 of ART-mediated viral suppression of <400 copies/mL (B) and subsequent mortality was assessed with Kaplan-Meier methods. The KT ratio at each time point was assessed in tertiles, and P values reflect findings from tests for trend.

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