Abstract
PURPOSE: HIV-1 disrupts the metabolic profile of people living with HIV (PLWH), including the Tryptophan-Kynurenine (Trp-Kyn) pathway, linked to disease outcomes and comorbidities. Despite numerous studies, consensus on key dysregulated metabolites in antiretroviral therapy (ART)-treated PLWH is lacking. This systematic review compiles data to identify and highlight the most noteworthy Trp-Kyn metabolites. METHODS: PubMed, Scopus, and Web of Science databases were searched using a search protocol specifically designed for this study. Studies that investigated the levels of metabolites in the Trp-Kyn pathway in the peripheral blood of PLWH on ART, as well as in healthy control groups were included. RESULTS: Thirteen metabolomic studies that investigated this pathway met our inclusion criteria. The findings revealed that Trp, Kyn, and the Kyn/Trp ratio (indicative of indoleamine 2,3-dioxygenase IDO activity) were the most investigated metabolites in this metabolic pathway. Evidence consistently demonstrated that Trp levels were lower in PLWH, while predicted IDO activity was consistently higher. Despite the widespread investigation of Kyn, there was no clear consensus on its levels in PLWH, with some studies reporting higher levels and others finding no significant differences compared to HIV-negative controls. CONCLUSION: In the modern ART era, Trp metabolism and IDO activity may play key regulatory roles in HIV-1 pathogenesis, as evidenced by the consistent patterns observed across various studies. These metabolites and related pathways warrant further investigation as potential targets for improved diagnostics, prognostics, and therapeutics in the context of HIV-1.