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

J Infect Dis. 2014 Aug 1;210(3):383-91. doi: 10.1093/infdis/jiu115. Epub 2014 Feb 28.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-HIV Agents / therapeutic use*
  • CD4 Lymphocyte Count
  • CD4-Positive T-Lymphocytes / physiology*
  • Female
  • HIV Infections / drug therapy*
  • HIV Infections / epidemiology
  • HIV Infections / immunology*
  • HIV Infections / mortality
  • Humans
  • Kynurenine / metabolism*
  • Male
  • Tryptophan / metabolism*
  • Uganda / epidemiology

Substances

  • Anti-HIV Agents
  • Kynurenine
  • Tryptophan