Untargeted GC/TOFMS unravel metabolic profiles in cerebrospinal fluid of Chinese people living with HIV

Abstract

Background: Metabolic syndrome becomes a focus of clinical cares to people living with HIV (PLHIV) globally. This study aimed to explore the metabolic profiles in cerebrospinal fluid (CSF) of Chinese people living with HIV (PLHIV). Methods: Cerebrospinal fluid samples from PLHIV and healthy controls were collected from our hospital. Then, the metabolic profiles of CSFs were analyzed PLHIV with healthy individual as the normal controls using the untargeted GC/TOFMS. Following this, kyoto encyclopedia of genes and genomes annotation and pathway analysis were performed to further explore the underlying mechanism of these metabolic alterations in cognitive impairment of PLHIV. Results: Both PCA analysis and OPLS-DA had presented that most samples were localized in 95% CI and the gap between control and HIV could significantly separate from each other. Upon this quality control, a total of 82 known metabolites were identified in CSF between PLHIV and healthy controls. Clustering of these metabolites presented that these differentially expressed metabolites could markedly distinguish HIV from healthy controls. Further pathway analyses showed that TCA cycle (citric acid, fumaric acid, lactate, et al.), amino acid (arginine, proline, alanine, aspartate, glutamine, et al.), lipid (cholesterol, butyrate, et al.) metabolisms were significantly changed in CSF of PLHIV, which might affect the cognitive status of PLHIV via affecting neuron energy support, signaling transduction, and neuroinflammation. Conclusion: Metabolic profiles were significantly altered in CSF and might play key roles in the etiology of cognitive impairment of PHLIV. Further explore the exact mechanism for these metabolic changes might be useful for cognitive impairment management of PHLIV. K E Y W O R D S cerebrospinal fluid, HIV-associated neurocognitive disorder, human immunodeficiency virus, metabonomic, untargeted GC/TOFMS This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

1H-NMR metabolomics investigation of CSF from children with HIV reveals altered neuroenergetics due to persistent immune activation

“…However, a calcium overload in the neurons, induced by astrocyte dysfunction and oxidative damage, also likely triggers increased tricarboxylic acid (TCA) cycle activity. Significantly decreased ketones (acetone and 3-hydroxybutyrate) in the HIV+ group in this study are consistent with the findings of Keram et al (2021) and Deme et al (2022), but in contrast to the results of Cassol et al (2014). The significantly elevated (p = 0.049) myo-inositol levels (590.64 ± 509.20) detected in the CSF of the HIV+ group, compared to the controls (244.82 ± 107.37) is indicative of astrocyte activation.…”

An exploratory investigation of the CSF metabolic profile of HIV in a South African paediatric cohort using GCxGC-TOF/MS

“…The acetyl-CoA released can be catabolized to produce ketone bodies for energy (Kassel et al, 1986 ). Reduced 3-hydroxybutyric acid in HIV-infected participants was also reported by Keram et al ( 2021 ) and Deme et al ( 2022 ) but contradicts the findings of Cassol et al ( 2014 ). However, ART exposure normalizes serum ketone body levels (Deme et al, 2022 ).…”

“…Acetyl-CoA is directed toward fatty acid synthesis, for the generation of longer-chain fatty acids used for viral budding, and post-translational modification of viral proteins via an HIV-induced increase in fatty acid synthase activity (Deme et al, 2022 ; Kulkarni et al, 2017 ). HIV-induced dyslipidaemia is associated with cognitive impairment (Keram et al, 2021 ), possibly partially mediated by reduced bodies of ketones of the CSF, especially in children, because the brain is highly dependent on them during the developmental stages. Tissue culture experiments found that the treatment of neurons with ketone bodies was protective against transactivator of transcription (tat)-induced damage by reducing reactive oxygen species (ROS), lowering intracellular calcium levels, and restoring the mitochondrial membrane potential (Deme et al, 2020 ).…”

Exploring salivary metabolome alterations in people with HIV: towards early diagnostic markers

“…Despite enrichment of the TCA cycle discovered in saliva exposome-wide association studies (EWAS) ( 25 ), research focusing on the salivary metabolites of PLWH remains scarce. Studies have shown that the TCA cycle is the most significantly altered metabolic pathway in the cerebrospinal fluid of people living with PLWH, affecting other amino acid and lipid metabolisms ( 26 ).…”

“…Citric acid, reversibly converted to cis-aconitic acid and isocitric acid under the action of aconitase, undergoes changes in the cerebrospinal fluid metabolism of PLWH. Accumulation of citric acid could potentially lead to cognitive deterioration in patients ( 26 , 27 ), suggesting its harmful role in the progression of HIV. In the CD4-L group (CD4 count <200/mm3), the accumulation of citric acid was significantly higher than in the CD4-M, CD4-H, and other post-treatment groups.…”