Role of HIV on Glutathione Synthesis and Oxidative Stress

HIV infection is associated the development of HIV associated dyslipidemic lipodystrophy
(HADL) as a metabolic complication, and we have previously shown that these patients have
abnormal lipid kinetics. HIV patients with lipodystrophy have been reported to have
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 with
lipodystrophy, 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 defective synthesis underlies GSH deficiency in patients with HIV lipodystrophy, and
will test a simple, inexpensive and rational therapy based on protein supplementation to
improve GSH synthesis and GSH concentrations in these patients. We will also measure plasma
oxidative stress, markers of oxidant damage and lipid kinetics in these subjects.