Plasma Tryptophan-Kynurenine Metabolites Are Altered in Human Immunodeficiency Virus Infection and Associated With Progression of Carotid Artery Atherosclerosis

Abstract

Background: It is unknown whether disrupted tryptophan catabolism is associated with cardiovascular disease (CVD) in human immunodeficiency virus (HIV)-infected individuals.

Methods: Plasma tryptophan and kynurenic acid were measured in 737 women and men (520 HIV+, 217 HIV-) from the Women's Interagency HIV Study and the Multicenter AIDS Cohort Study. Repeated B-mode carotid artery ultrasound imaging was obtained from 2004 through 2013. We examined associations of baseline tryptophan, kynurenic acid, and kynurenic acid-to-tryptophan (KYNA/TRP) ratio, with risk of carotid plaque.

Results: After a 7-year follow-up, 112 participants developed carotid plaque. Compared to those without HIV infection, HIV-infected participants had lower tryptophan (P < .001), higher KYNA/TRP (P = .01), and similar kynurenic acid levels (P = .51). Tryptophan, kynurenic acid, and KYNA/TRP were correlated with T-cell activation (CD38+HLA-DR+) and immune activation markers (serum sCD14, galectin-3) but had few correlations with interleukin-6, C-reactive protein, or CVD risk factors (blood pressure, lipids). Adjusted for demographic and behavioral factors, each standard deviation (SD) increment in tryptophan was associated with a 29% (95% confidence interval [CI], 17%-38%) decreased risk of carotid plaque (P < .001), while each SD increment in kynurenic acid (P = .02) and KYNA/TRP (P < .001) was associated with a 34% (6%-69%) and a 47% (26%-73%) increased risk of carotid plaque, respectively. After further adjustment for CVD risk factors and immune activation markers, these associations were attenuated but remained significant.

Conclusions: Plasma tryptophan-kynurenine metabolites are altered in HIV infection and associated with progression of carotid artery atherosclerosis.

Figure 1.

Plasma tryptophan, kynurenic acid and kynurenic acid-to-tryptophan (KYNA/TRP) ratio between human immunodeficiency virus (HIV)–infected and HIV-uninfected participants. Data are raw values (area under the curve of metabolite peaks) of plasma tryptophan, kynurenic acid, and KYNA/TRP ratio in a logarithmic scale among 217 HIV-uninfected, 290 HIV-infected aviremic (undetectable viral load ≤80 copies/mL), and 230 HIV-infected viremic (viral load >80 copies/mL) individuals. P for trend <0.001, <0.001, and = 0.86 for tryptophan, kynurenic acid, and KYNA/TRP ratio, respectively, across 3 groups. *P < .05 for pairwise comparison between HIV+ aviremic group or HIV+ viremic group vs HIV-uninfected group, controlling for multiple testing. Abbreviations: HIV, human immunodeficiency virus; KYNA/TRP, kynurenic acid-to-tryptophan.

Figure 2.

Associations of plasma tryptophan, kynurenic acid, and kynurenic acid-to-tryptophan ratio with risk of carotid artery plaque in human immunodeficiency virus (HIV)–uninfected, HIV+ persistently virologically suppressed, and HIV+ virologically unsuppressed participants. Data are risk ratio (95% confidence interval) on risk of carotid artery plaque per standard deviation increment in log-transformed metabolite variables, adjusted for age, sex, race/ethnicity, education, study site, current smoking, history of hepatitis C virus, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, antihypertensive medication use, lipid lowering medication use, and body mass index. HIV+ persistently virologically suppressed participants were defined as participants who had consistent plasma HIV RNA levels <80 copies/mL simultaneous with continuous antiretroviral therapy use over the study period. Abbreviations: CI, confidence interval; HIV, human immunodeficiency virus; KYNA/TRP, kynurenic acid-to-tryptophan; SD, standard deviation.