Tryptophan-kynurenine metabolic pathway and daytime dysfunction in women with HIV

Abstract

Sleep disturbances are prevalent in women with HIV (WWH). Tryptophan-kynurenine (T-K) pathway metabolites are associated with alterations in actigraphy derived sleep measures in WWH, although may not always correlate with functional impairment. We investigated the relationship between T-K pathway metabolites and self-reported daytime dysfunction in WWH and women without HIV (WWoH). 141 WWH on stable antiretroviral therapy and 140 demographically similar WWoH enrolled in the IDOze Study had targeted plasma T-K metabolites measured using liquid chromatography-tandem mass spectrometry. We utilized the daytime dysfunction component of the Pittsburgh Sleep Quality Index (PSQI) to assess functional impairment across HIV-serostatus. Lower levels of 5-hydroxytryptophan and serotonin were associated with greater daytime dysfunction in all women. In WWH, daytime dysfunction was associated with increased kynurenic acid (R = 0.26, p < 0.05), and kynurenic acid-tryptophan (KA-T) ratio (R = 0.28, p < 0.01). WWH with daytime dysfunction had a 0.7 log fold increase in kynurenic acid compared to WWH without daytime dysfunction. Kynurenic acid levels and the KA-T ratio were associated with daytime dysfunction in WWH but not in WWoH. Longitudinal studies are needed to establish a causal relationship and directionality between T-K metabolic changes and sleep impairment in WWH.

Keywords: HIV infection; Kynurenine; Metabolomics; Sleep; Tryptophan; Women.

Figure 1:. Heatmap of correlations between daytime dysfunction and metabolites in the tryptophan-kynurenine pathway for women with HIV (WWH), WWoH, viremic WWH and aviremic WWH.

Daytime dysfunction scores on the Pittsburgh Sleep Quality Index (PSQI) were correlated to log metabolite abundances in the T-K pathway in WWH (n=141), WWoH (n=140), viremic WWH (n=25) and aviremic WWH(n=116). Viremia was defined as >20 copies/ml of HIV RNA in serum. Spearman’s R was used to calculate the correlation coefficient for multivariate analysis controlling for age, race, menopausal status, CESD-affect score. Tiles with no stars indicate no statistical significance, * = p<0.05, ** = p<0.01. HIV = human immunodeficiency virus; CESD = Center for Epidemiological Studies – Depression Scale; K-T = kynurenine-tryptophan; KA-T = kynurenic-acid-tryptophan.

Figure 2:. Log fold differences in metabolite abundances for those with versus without daytime dysfunction in women with HIV (WWH) and without HIV (WWoH).

Presence of daytime dysfunction considered if PSQI daytime dysfunction score was >=1. Comparison within WWH (n=141) group shown in top panel, comparison within WWoH (n=140) shown in bottom panel. Metabolites are colored based on the log fold relative abundance differences in those with versus without daytime dysfunction. Melatonin is colored grey as it was not measured. Single bold border represents statistical significance at p<0.05, double bold border represents significance at p<0.01, triple bold border represents significance at p<0.001. All associations were adjusted for age, race, menopausal status, and CESD-affect score. Not all metabolites in the T-K pathway are shown here. HIV = human immunodeficiency virus; PSQI = Pittsburgh Sleep Quality Index; CESD = Center for Epidemiological Studies – Depression Scale.