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

Helen Byakwaga, Yap Boum, Yong Huang, Conrad Muzoora, Annet Kembabazi, Sheri D. Weiser, John Bennett, Huyen Cao, Jessica E. Haberer, Steven G. Deeks, David Bangsberg, Joseph M. McCune, Jeffrey N. Martin, Peter W. Hunt

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)383-391
Number of pages9
JournalJournal of Infectious Diseases
Volume210
Issue number3
DOIs
StatePublished - Aug 1 2014
Externally publishedYes

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Kynurenine
Tryptophan
CD4 Lymphocyte Count
HIV
T-Lymphocytes
Mortality
Indoleamine-Pyrrole 2,3,-Dioxygenase
Virus Diseases
Viruses
Therapeutics
Interleukin-17
Dendritic Cells
Lipopolysaccharides
Monocytes
Body Mass Index
Cell Proliferation

Keywords

  • Antiretroviral therapy
  • HIV
  • Indoleamine 2,3-dioxygenase-1
  • Kynurenine
  • Mortality
  • Tryptophan
  • Uganda

ASJC Scopus subject areas

  • Infectious Diseases
  • Immunology and Allergy

Cite this

The kynurenine pathway of tryptophan catabolism, CD4+ T-cell recovery, and mortality among HIV-infected Ugandans initiating antiretroviral therapy. / Byakwaga, Helen; Boum, Yap; Huang, Yong; Muzoora, Conrad; Kembabazi, Annet; Weiser, Sheri D.; Bennett, John; Cao, Huyen; Haberer, Jessica E.; Deeks, Steven G.; Bangsberg, David; McCune, Joseph M.; Martin, Jeffrey N.; Hunt, Peter W.

In: Journal of Infectious Diseases, Vol. 210, No. 3, 01.08.2014, p. 383-391.

Research output: Contribution to journalArticle

Byakwaga, H, Boum, Y, Huang, Y, Muzoora, C, Kembabazi, A, Weiser, SD, Bennett, J, Cao, H, Haberer, JE, Deeks, SG, Bangsberg, D, McCune, JM, Martin, JN & Hunt, PW 2014, 'The kynurenine pathway of tryptophan catabolism, CD4+ T-cell recovery, and mortality among HIV-infected Ugandans initiating antiretroviral therapy', Journal of Infectious Diseases, vol. 210, no. 3, pp. 383-391. https://doi.org/10.1093/infdis/jiu115
Byakwaga, Helen ; Boum, Yap ; Huang, Yong ; Muzoora, Conrad ; Kembabazi, Annet ; Weiser, Sheri D. ; Bennett, John ; Cao, Huyen ; Haberer, Jessica E. ; Deeks, Steven G. ; Bangsberg, David ; McCune, Joseph M. ; Martin, Jeffrey N. ; Hunt, Peter W. / The kynurenine pathway of tryptophan catabolism, CD4+ T-cell recovery, and mortality among HIV-infected Ugandans initiating antiretroviral therapy. In: Journal of Infectious Diseases. 2014 ; Vol. 210, No. 3. pp. 383-391.
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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.",
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T1 - The kynurenine pathway of tryptophan catabolism, CD4+ T-cell recovery, and mortality among HIV-infected Ugandans initiating antiretroviral therapy

AU - Byakwaga, Helen

AU - Boum, Yap

AU - Huang, Yong

AU - Muzoora, Conrad

AU - Kembabazi, Annet

AU - Weiser, Sheri D.

AU - Bennett, John

AU - Cao, Huyen

AU - Haberer, Jessica E.

AU - Deeks, Steven G.

AU - Bangsberg, David

AU - McCune, Joseph M.

AU - Martin, Jeffrey N.

AU - Hunt, Peter W.

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N2 - 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.

AB - 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.

KW - Antiretroviral therapy

KW - HIV

KW - Indoleamine 2,3-dioxygenase-1

KW - Kynurenine

KW - Mortality

KW - Tryptophan

KW - Uganda

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