Role of HIV on Glutathione Synthesis and Oxidative Stress

HIV infection is associated the development of increased oxidative stress and deficiency of glutathione (GSH), the dominant endogenous antioxidant protein, but the underlying mechanisms contributing to GSH deficiency are hitherto unknown. Furthermore GSH metabolism has not been studied in HIV patients, in whom the burden of risk factors promoting oxidative stress is highest. Our previous studies in non-HIV human subjects with diabetes-related oxidative stress and GSH deficiency have demonstrated that the latter is due to decreased synthesis of GSH. Importantly, short-term dietary supplementation with the simple GSH precursor amino-acids cysteine and glycine, boosted GSH synthesis and cellular concentrations, corrected GSH deficiency, and reduced oxidative stress and oxidant damage. The current proposal will study whether (1) defective synthesis underlies GSH deficiency in patients with HIV, and will test a simple, inexpensive and rational therapy based on protein supplementation to improve GSH synthesis and concentrations and lower markers of oxidative stress and oxidant damage in these patients; (2) study if correction of GSH deficiency is asssociated with any changes in (a) impaired mitochondrial fuel oxidation in the fasted and insulin stimulated states; (b) insulin sensitivity; (c) body composition and anthropometry; (d) forearm muscle strength; (e) plasma biochemistry, and (f) quality of life indices in these subjects.

Subjects will be studied before and after receiving oral cysteine (as n-acetylcysteine) and glycine for 2 weeks

Cysteine and glycine will be supplemented at doses of 0.81 mmol/kg/d and 1.31 mmol/kg/d for 2 weeks each

Measure rate of lipolysis (from infused 13C-palmitate) and recovery of 13CO2 (from infused acetate tracer)

Inclusion Criteria: (1) HIV infected patients with GSH deficiency Exclusion Criteria: renal impairment (serum Creatinine above 1.5mg/dL), liver impairment (ALT and AST > 2x upper limit of normal) any hormonal disorders such as hypothyroidism, hypercortisolemia, hypogonadism, or diabetes mellitus on pharmacotherapy evidence of infections other than HIV in the preceding 3 months subjects with plasma triglyceride concentrations of ≥ 500mg/dL on triglyceride lowering therapy BMI < 20 established heart disease Co-existing viral hepatitis B and C