Altered plasma metabolic profiles in untreated HIV-infected patients

To characterized metabolic alterations experienced during an untreated HIV-1 infection, we compared 18 untreated HIV-1-infected patients (population A) with 23 controls through profiling their biogenic amines, lipids, and signalling lipid metabolites. As shown in the volcano plot in Fig. 1a, 18 biogenic amines were differently affected in HIV patients versus controls, with reduced levels in all (see Supplementary Table S1). Reduced levels of antioxidants, including total glutathione and taurine, together with lipid headgroup moieties o-phosphoethanolamine and the choline metabolite sarcosine were identified as the most significantly altered amine metabolites during an untreated HIV infection. Furthermore, untreated HIV patients had decreased levels of tryptophan and serotonin compared to controls. The plasma kynurenine/tryptophan (K/T) ratio, as a readout for indoleamine 2,3-dioxygenase (IDO) activity, showed upregulated IDO activity during untreated HIV infection compared to controls (p = 0.0003) (see Supplementary Fig. S1A). Concurrently investigating the plasma serotonin/tryptophan ratio reflected the consequences of increased IDO activity for serotonin synthesis during untreated HIV infection compared to controls (p < 0.0001) (see Supplementary Fig. S1B). Decreased levels of the branch chain amino acids leucine and isoleucine as well as carnosine reflected impaired muscle metabolism during an untreated HIV infection. The significantly decreased levels of ornithine and putrescine in untreated HIV patients also hints at a reduced urea cycle and thus ammonia clearance in these patients compared to controls. Additionally, decreased levels of alanine, asparagine, α-aminobutyric acid, tyrosine, and methionine were also detected in untreated HIV patients compared to controls. Evaluation of the levels of plasma lipids, which included the different lysophospholipids classes, phospholipids, di/triglycerides, sphingomyelins, ceramides, and cholesterol esters, revealed 44 modulated metabolites with a p < 0.05 and a fold-change (FC) ≥ 1.30 or ≤0.70 (Fig. 1b and Supplementary Table S2). The lysophospholipids class presented with 6 lysophosphatidic acid (LPA) species having increased plasma levels in untreated HIV-infected patients versus controls, and one lysophosphatidylcholine (LPC) metabolite which was reduced compared to controls. Furthermore, two monounsaturated sphingomyelin (SM) species, two PUFA cholesterol ester (CE), and two long-chain saturated ceramides (CER) metabolites all had reduced levels in untreated HIV patients. The triglycerides (TG) profile presented with 14 mostly polyunsaturated triglycerides species showing significantly increased levels during untreated HIV infection. The phospholipids presented with seven phosphatidylcholines (PC), four plasmalogen phosphatidylcholines (PC-O), two phosphatidylethanolamines (PE) and two plasmalogen phosphatidylethanolamines (PE-O) all having decreased levels during untreated HIV.The third subclass of metabolites that were evaluated for differences between untreated HIV patients and controls was the class of signalling lipid mediators, derived from the enzymatic or free radical oxidised polyunsaturated fatty acids, which includes the prostaglandins, thromboxanes, hydroxy-fatty acids, leukotrienes, resolvins, epoxy-fatty acids, isoprostanes and nitro fatty acids. During the untreated HIV infection 22 significantly affected signalling lipid metabolites were identified of which 8 had reduced levels and 14 had increased levels in the untreated HIV patients compared to controls. (Fig. 1c, Supplementary Table S3). The four signalling mediators: 5,6-DiHETrE, 8,9-DiHETrE, 11,12-DiHETrE, and 14,15-DiHETrE all derived from arachidonic acid and synthesised by cytochrome P450 isozymes showed the most significant increased levels in the untreated HIV patients compared to the controls. Furthermore, untreated HIV patients had increased levels of dihydrosphingosine but decreased levels of three different Sphingosine-1-phosphate species compared to controls. The metabolites 5-HETE, 12-HETE and 15-HETE derived from the Lipoxygenase activity on Arachidonic acid, also had increased levels compared to the controls. Oxidized lipids due to the activity of ROS and RNS showed differential responses with increased levels of 8-iso-PGE2, 2,3-dinor-PGF2a and 20 HETE and decreased levels of 11-HDoHE and 8,12-iPF2α-IV in untreated HIV patients compared to controls.

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