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Tryptophan metabolism and its relationship with immune activation, depression, and neurocognitive impairment among HIV-infected individuals

  • Author(s): Keegan, MR
  • Chittiprol, S
  • Winston, A
  • Letendre, S
  • Fuchs, D
  • Boasso, A
  • Ellis, RJ
  • et al.
Abstract

OBJECTIVE: Cognitive impairment (CI) and major depressive disorder (MDD) remain prevalent in treated HIV-1 disease; however, the pathogenesis remains elusive. A possible contributing mechanism is immune-mediated degradation of tryptophan (TRP) via the kynurenine (KYN) pathway, resulting in decreased production of serotonin and accumulation of TRP degradation products. We explored the association of these biochemical pathways and their relationship with CI and MDD in HIV-positive (HIV+) individuals. METHODS: In a cross-sectional analysis, concentrations of neopterin (NEO), tumor necrosis factor-alpha, TRP, KYN, KYN/TRP ratio, phenylalanine (PHE), tyrosine (TYR), PHE/TYR ratio, and nitrite were assessed in the cerebrospinal fluid (CSF) and plasma of HIV+ (n = 91) and HIV-negative (HIV-) individuals (n = 66). CI and MDD were assessed via a comprehensive neuropsychological test battery. A Global Deficit Score ≥0.5 was defined as CI. Nonparametric statistical analyses included Kruskal-Wallis and Mann-Whitney U tests, and multivariate logistic regression. RESULTS: Following Bonferroni correction, NEO concentrations were found to be greater in CSF and TRP concentration was found to be lower in the plasma of HIV+ versus HIV- individuals, including a subgroup of aviremic (defined as HIV-1 RNA <50 cps/mL) HIV+ participants receiving antiretroviral therapy (n = 44). There was a nonsignificant trend toward higher KYN/TRP ratios in plasma in the HIV+ group (P = 0.027; Bonferroni corrected α = 0.0027). In a logistic regression model, lower KYN/TRP ratios in plasma were associated with CI and MDD in the overall HIV+ group (P = 0.038 and P = 0.063, respectively) and the aviremic subgroup (P = 0.066 and P = 0.027, respectively), though this observation was not statistically significant following Bonferroni correction (Bonferroni corrected α = 0.0031). CONCLUSIONS: We observed a trend toward lower KYN/TRP ratios in aviremic HIV+ patients with CI and MDD.

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