Uridine Metabolism in HIV-1-Infected Patients: Effect of Infection, of Antiretroviral Therapy and of HIV-1/ART-Associated Lipodystrophy Syndrome

Pere Domingo,Javier Torres-Torronteras,Irene Fernandez,Marta Giralt,José M Gallego-Escuredo,Marçal Pastor-Anglada,Pedro Cano-Soldado,Joan Carles Domingo,Virginia Pomar,Maria Gracia Mateo,Francesc Vidal,Ramon Marti,Francesc Villarroya,Maria Del Mar Gutierrez,Antoni Andreu,Gary Maartens

doi:10.1371/journal.pone.0013896

Abstract

BackgroundUridine has been advocated for the treatment of HIV-1/HAART-associated lipodystrophy (HALS), although its metabolism in HIV-1-infected patients is poorly understood.MethodsPlasma uridine concentrations were measured in 35 controls and 221 HIV-1-infected patients and fat uridine in 15 controls and 19 patients. The diagnosis of HALS was performed following the criteria of the Lipodystrophy Severity Grading Scale. Uridine was measured by a binary gradient-elution HPLC method. Analysis of genes encoding uridine metabolizing enzymes in fat was performed with TaqMan RT-PCR.ResultsMedian plasma uridine concentrations for HIV-1-infected patients were 3.80 µmol/l (interquartile range: 1.60), and for controls 4.60 µmol/l (IQR: 1.8) (P = 0.0009). In fat, they were of 6.0 (3.67), and 2.8 (4.65) nmol/mg of protein, respectively (P = 0.0118). Patients with a mixed HALS form had a median plasma uridine level of 4.0 (IC95%: 3.40–4.80) whereas in those with isolated lipoatrophy it was 3.25 (2.55–4.15) µmol/l/l (P = 0.0066). The expression of uridine cytidine kinase and uridine phosphorylase genes was significantly decreased in all groups of patients with respect to controls. A higher expression of the mRNAs for concentrative nucleoside transporters was found in HIV-1-infected patients with respect to healthy controls.ConclusionsHIV-1 infection is associated with a decrease in plasma uridine and a shift of uridine to the adipose tissue compartment. Antiretroviral therapy was not associated with plasma uridine concentrations, but pure lipoatrophic HALS was associated with significantly lower plasma uridine concentrations.

Highlights

Pyrimidines are synthesized de novo through a multistep process starting from glutamine and carbon dioxide to form the pyrimidine ring, orotic acid [1]
The synthesis of orotic acid is catalyzed by dihydroorotate dehydrogenase (DHODH), an enzyme located in the inner mitochondrial membrane, and functional connection to the respiratory chain via ubiquinone ensures efficient oxidation of dihydroorotate [2]
The demographics, HIV-1 infection, and antiretroviral exposure parameters from patients and controls are shown in table 1

Summary

Introduction

Pyrimidines are synthesized de novo through a multistep process starting from glutamine and carbon dioxide to form the pyrimidine ring, orotic acid [1]. Orotate is converted to its nucleotide form in the presence of 5-phosphorylribose-pyrophosphate. Orotate monophosphate is converted by a multifunctional enzyme, uridine monophosphate (UMP) synthase to the nucleotide UMP (Figure 1). A large portion of the pyrimidines are salvaged from the degradation of the nucleic acids and nucleotides [4]. The liver appears to have this homeostatic control on uridine degradation and formation [7]. Uridine is essentially cleared in a single pass through the liver and is replaced by ‘‘new uridine’’ formed by de novo synthesis [7]. Uridine has been advocated for the treatment of HIV-1/HAART-associated lipodystrophy (HALS), its metabolism in HIV-1-infected patients is poorly understood

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