Kynurenine Pathway Activation is Associated with Poor Sleep Efficiency in Men With HIV

Abstract

Background: Sleep disturbances are common in people with HIV, yet the underlying biological mechanisms remain poorly understood. Chronic immune activation in HIV can induce the tryptophan-kynurenine (TK) pathway, which both reduces melatonin synthesis and increases production of neurotoxic metabolites. TK pathway activation in women with HIV has been linked to fragmented sleep. Whether similar associations exist in men remains unclear, as men may exhibit different inflammatory and metabolic profiles. Method: We studied men with and without HIV (MWH/MWoH) from the Multicenter AIDS Cohort Study (MACS) who underwent actigraphy. TK pathway metabolites were directly quantified in contemporaneous plasma using liquid chromatography–tandem mass spectrometry. Partial correlation models adjusting for covariates examined relationships between TK metabolites and actigraphy-based sleep metrics by HIV status. Results: MWH (n=346) were slightly younger (mean age: 54 vs 61 yr) and more likely to be black (32% vs. 20%) than MWoH (n=304). The vast majority (96%) of MWH were virally suppressed. MWH had lower sleep efficiency, 86.6% vs 88.5% (p<0.001) than MWoH. MWH had lower tryptophan and higher kynurenine levels, indicative of TK pathway activation, and higher levels of the neurotoxic downstream kynurenine metabolites 3-hydroxykynurenine (3-HK) and quinolinic acid (QA). Higher KT ratio and 3-HK and QA levels were associated with lower sleep efficiency in MWH after multivariable adjustment. Conclusion: TK pathway activation and higher neurotoxic metabolites (3-HK, QA) were associated with poorer sleep efficiency among MWH but not MWoH. Further research exploring causal mechanisms is required to develop targeted strategies for improving sleep in this population.

The authors' abstract, as published at the source. JAIDS Journal of Acquired Immune Deficiency Syndromes, 2026 · DOI ↗