Tryptophan-Kynurenine Pathway Activation and Cognition in Virally Suppressed Women With HIV

Background: Immune and cognitive dysfunction persists even in virally suppressed women with HIV (VS-WWH). Since inflammation and HIV proteins induce the enzyme indoleamine 2,3-dioxygenase (IDO), converting tryptophan (T) to kynurenine (K) while producing downstream neurotoxic metabolites, we investigated IDO activation (KT ratio) in relation to cognition in VS-WWH and demographically similar women without HIV (WWoH).

Methods: Ninety-nine VS-WWH on stable antiretroviral therapy and 102 WWoH (median age 52 vs 54 years; 73% vs 74% Black, respectively) from the New York and Chicago sites of the Women's Interagency HIV Study (WIHS) completed a neuropsychological test battery assessing motor function, processing speed, attention/working memory, verbal fluency, verbal learning and memory, and executive function and had plasma measured for tryptophan-kynurenine metabolites through liquid chromatography-tandem mass spectrometry and monocyte-derived [soluble cluster of differentiation-14 (sCD14), soluble cluster of differentiation-163 (sCD163), monocyte chemoattractant protein-1 (MCP-1)] plus general inflammatory markers [tumor necrosis factor alpha-2 receptor (TNF-R2), high-sensitivity C-reactive protein, high-sensitivity interleukin-6] through enzyme-linked immunosorbent assays between 2017 and 2020.

Results: VS-WWH had a higher KT ratio (P < 0.01) and higher sCD14 levels (P < 0.05) compared with WWoH. Higher sCD163 was associated with higher KT ratio (R = 0.29, P < 0.01) and worse fine motor function in VS-WWH; after adjusting for sCD163 and sCD14 in multivariable regressions, higher KT ratio remained significantly associated with impaired fine motor function in VS-WWH only (standardized β = -0.29, P < 0.05). IDO activation was not associated with cognition in WWoH.

Conclusions: IDO activation (K:T) was associated with worse fine motor control in VS-WWH independent of measured systemic inflammation. Further studies investigating biological mechanisms linking IDO activation to fine motor function among VS-WWH are warranted.