Tryptophan Metabolism and Its Relationship with Depression and Cognitive Impairment Among HIV-infected Individuals.
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-WhitneyUtests, 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 correctedα= 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 andP= 0.063, respectively) and the aviremic subgroup (P= 0.066 andP= 0.027, respectively), though this observation was not statistically significant following Bonferroni correction (Bonferroni correctedα= 0.0031).


CONCLUSIONS
We observed a trend toward lower KYN/TRP ratios in aviremic HIV+ patients with CI and MDD.
Imperial College London, Department of Medicine, London, United Kingdom.; ViiV Healthcare Ltd., Clinical Sciences Group, London, United Kingdom.
Michael R
MR
Keegan
University of California, San Diego, Departments of Neurosciences and Psychiatry, San Diego, CA, USA.; Memorial Healthcare System, Department of Pathology, Hollywood, FL, USA.
Seetharamaiah
S
Chittiprol
University of California, San Diego, Departments of Neurosciences and Psychiatry, San Diego, CA, USA.
Scott L
SL
Letendre
Imperial College London, Department of Medicine, London, United Kingdom.
Alan
A
Winston
Innsbruck Medical University, Centre for Chemistry and Biomedicine, Innsbruck, Austria.
Dietmar
D
Fuchs
Imperial College London, Centre for Immunology and Vaccinology, London, United Kingdom.
Adriano
A
Boasso
University of California, San Diego, Departments of Neurosciences and Psychiatry, San Diego, CA, USA.
Jennifer
J
Iudicello
University of California, San Diego, Departments of Neurosciences and Psychiatry, San Diego, CA, USA.
Ronald J
RJ
Ellis
HIV; IDO; cognitive impairment; depression; kynurenine; tryptophan