title: The kynurenine pathway of tryptophan catabolism, CD4+ T-cell recovery, and mortality among HIV-infected Ugandans initiating antiretroviral therapy.
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.
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco Faculty of Medicine, Mbarara University of Science and Technology.
authors.forename: Helen
authors.initials: H
authors.lastname: Byakwaga
authors.affiliation: Faculty of Medicine, Mbarara University of Science and Technology Epicentre Mbarara research Base, Uganda.
authors.forename: Yap
authors.initials: Y
authors.lastname: Boum
authors.affiliation: Department of Bioengineering and Therapeutic Sciences.
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Faculty of Medicine, Mbarara University of Science and Technology.
authors.forename: Conrad
authors.initials: C
authors.lastname: Muzoora
authors.affiliation: Faculty of Medicine, Mbarara University of Science and Technology.
authors.forename: Annet
authors.initials: A
authors.lastname: Kembabazi
authors.affiliation: Department of Medicine, University of California, San Francisco.
authors.forename: Sheri D
authors.initials: SD
authors.lastname: Weiser
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco.
authors.forename: John
authors.initials: J
authors.lastname: Bennett
authors.affiliation: California Department of Public Health, Richmond, CA.
authors.forename: Huyen
authors.initials: H
authors.lastname: Cao
authors.affiliation: Department of Medicine, Harvard Medical School Center for Global Health, Massachusetts General Hospital, Boston, MA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Haberer
authors.affiliation: Department of Medicine, University of California, San Francisco.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.affiliation: Center for Global Health, Massachusetts General Hospital, Boston, MA Department of Global Health and Populations, Harvard School of Public Health Ragon Institute of MGH, MIT and Harvard.
authors.forename: David R
authors.initials: DR
authors.lastname: Bangsberg
authors.affiliation: Department of Medicine, University of California, San Francisco.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: McCune
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Martin
authors.affiliation: Department of Medicine, University of California, San Francisco.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hunt
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000453:epidemiology / Q000276:immunology* / Q000401:mortality; D006801:Humans; D007737:Kynurenine / Q000378:metabolism*; D008297:Male; D014364:Tryptophan / Q000378:metabolism*; D014454:Uganda / Q000453:epidemiology
chemical_list: D019380:Anti-HIV Agents; D007737:Kynurenine; D014364:Tryptophan
keywords: HIV; Tryptophan; Uganda; antiretroviral therapy; indoleamine 2,3-dioxygenase-1; kynurenine; mortality