The IDOze Study: The Link Between Sleep Disruption and Tryptophan-Kynurenine Pathway Activation in Women With Human Immunodeficiency Virus

Abstract

Background: Poor sleep is associated with human immunodeficiency virus (HIV), particularly among women with HIV (WWH), although mechanisms are unclear. We explored cross-sectional associations between sleep disruption and tryptophan-kynurenine (T/K) pathway activation, measured by the kynurenine-to-tryptophan ratio (K:T).

Methods: HIV-uninfected women (HIV-) and WWH aged 35-70 years and on stable antiretroviral therapy were included. Sleep metrics were measured using wrist actigraphy. Plasma T/K pathway metabolites were measured using liquid chromatography-tandem mass spectrometry. Multivariate linear regression models examined relationships between K:T and actigraphy-based sleep metrics by HIV status.

Results: WWH (n = 153) and HIV- women (n = 151) were demographically similar. Among WWH, median CD4 was 751 cells/µL; 92% had undetectable HIV RNA. Compared to HIV- women, WWH had higher K:T (P < .001) and kynurenine (P = .01) levels but similar tryptophan levels (P = .25). Higher K:T was associated with more wake bouts (P = .001), more time awake after sleep onset (P = .01), and lower sleep efficiency (P = .03) in WWH only.

Conclusions: HIV infection was associated with T/K pathway activation; this activation was associated with poorer sleep efficiency and more fragmented sleep. While longitudinal studies are needed to elucidate the directionality of these associations, these findings may help identify treatments to reduce sleep disruption in WWH by targeting residual inflammation and T/K pathway activation.

Keywords: HIV infection; IDO-1; indoleamine 2, 3-dioxygenase; kynurenine; metabolomics; sleep; tryptophan; women.

Figure 1.

Plasma kynurenine, tryptophan, and kynurenine-to-tryptophan (K:T) ratio in human immunodeficiency virus (HIV)–uninfected (HIV^–) women vs viremic and aviremic women with HIV (HIV⁺). Data are the relative abundance of plasma tryptophan, kynurenine, and K:T ratio (%) among 26 HIV⁺ viremic (HIV RNA ≥20 copies/mL), 109 HIV⁺ aviremic (HIV RNA <20 copies/mL), and 151 HIV^– women. Not shown: Overall, women with HIV had higher K:T ratio (P < .001) and kynurenine (P = .01) compared to HIV^– women.

Figure 2.

Correlation heatmap of plasma tryptophan, kynurenine, and kynurenine-to-tryptophan (K:T) ratio with inflammatory markers in human immunodeficiency (HIV)–uninfected (HIV^–) participants, women with HIV (WWH), and overall (all participants). Data are unadjusted Spearman correlation coefficients of plasma tryptophan, kynurenine, and K:T ratio with high-sensitivity C-reactive protein (hsCRP) and serum levels of soluble CD14, CD163, CCL2, tumor necrosis factor alpha receptor 2 (TNF-RII), and high-sensitivity interleukin 6 (hsIL-6) among 26 viremic WWH (HIV RNA ≥20 copies/mL), 105 aviremic WWH, and 150 HIV^– women. *P < .05; **P < .01; ***P < .001.