Plasma Metabolomics Biosignature According to HIV Stage of Infection, Pace of Disease Progression, Viremia Level and Immunological Response to Treatment

Abstract

Background: We evaluated plasma samples HIV-infected individuals with different phenotypic profile among five HIV-infected elite controllers and five rapid progressors after recent HIV infection and one year later and from 10 individuals subjected to antiretroviral therapy, five of whom were immunological non-responders (INR), before and after one year of antiretroviral treatment compared to 175 samples from HIV-negative patients. A targeted quantitative tandem mass spectrometry metabolomics approach was used in order to determine plasma metabolomics biosignature that may relate to HIV infection, pace of HIV disease progression, and immunological response to treatment.

Results: Twenty-five unique metabolites were identified, including five metabolites that could distinguish rapid progressors and INRs at baseline. Severe deregulation in acylcarnitine and sphingomyelin metabolism compatible with mitochondrial deficiencies was observed. β-oxidation and sphingosine-1-phosphate-phosphatase-1 activity were down-regulated, whereas acyl-alkyl-containing phosphatidylcholines and alkylglyceronephosphate synthase levels were elevated in INRs. Evidence that elite controllers harbor an inborn error of metabolism (late-onset multiple acyl-coenzyme A dehydrogenase deficiency [MADD]) was detected.

Conclusions: Blood-based markers from metabolomics show a very high accuracy of discriminating HIV infection between varieties of controls and have the ability to predict rapid disease progression or poor antiretroviral immunological response. These metabolites can be used as biomarkers of HIV natural evolution or treatment response and provide insight into the mechanisms of the disease.

Fig 1. Unsupervised Heat map Clustering Analysis depicting identification of metabolites able to differentiate between Cases and Controls.

Fig 2

Proportion of Esterified to free Carnitines (Total AC/C0) (A; p = 9.8245E-11 and FDR = 4.1977–10), Beta oxidation (B; p = 1.3529E-13 and FDR = 8.4782E-13) Omega Oxidation (C; p = 6.9445E-11 and FDR = 3.1085E-10), Non-Essential Amino acids other than Glu and Asp (D; p = 1.5306E-47 and FDR = 7.1938E-46), sphingomyelin (E; p = 1.1088E-18 and FDR = 6.74E-19) and uptake of fatty acids to mitochondria (CPT1) (F; p = 0.0016126 and FDR = 0.0026136). Y Axis is depicting micro molar plasma concentrations. Cont = controls; Elite = elite controllers; RP = rapid progressors; IR = immunological responders; INR = immunological non-responders.

Fig 3. Histogram representing the mean Sphingosine‐1‐Phosphate Phosphatase 1 activity (ratio SGPP1) in different groups.

Sphingolipid metabolism is decreased in HIV patients compared to healthy controls (T Test = 0.012128) particularly in the INR group after antiretroviral treatment (arrow) as demonstrated by the ANOVA analysis of SGPP1 activity (p = 2.5266E-7, -log10(p) = 6.5975, FDR = 2.8123E-6). Y Axis is depicting micro molar plasma concentrations. Cont = controls; A1 and A2 are Elite controlers during recent infection and after one year of enrollment; B1 and B2 = Rapid Progressors during recent infection and after one year of enrollment; C1 and C2 = Immunologic Responders before treatment and after one year of treatment, D1 and D2 = INR before treatment and after one year of treatment.

Fig 4. Histogram representing the mean Ether lipid concentration in different groups.

Ether lipid production returns to normal levels after 1 year of follow-up except in the INR group (arrow, p = 1.1405E-5, -log10(p) = 4.9429, FDR = 9.6586E-5). Y Axis is depicting micro molar plasma concentrations. Cont = controls; A1 and A2 are Elite controllers during recent infection and after one year of enrollment; B1 and B2 = Rapid Progressors during recent infection and after one year of enrollment; C1 and C2 = Immunologic Responders before treatment and after one year of treatment; D1 and D2 = INR before treatment and after one year of treatment.