Role of HIV on Glutathione Synthesis and Oxidative Stress

Study Overview
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Brief Summary
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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.

Official Title
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Role of HIV on Glutathione Synthesis and Oxidative Stress

Conditions
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HIV Infection, Erythrocyte Glutathione Deficiency

Intervention / Treatment
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* Dietary Supplement: Cysteine (as n-acetylcysteine) and glycine
* Dietary Supplement: Cysteine/glycine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cysteine/glycine<br>Subjects will be studied before and after receiving oral cysteine (as n-acetylcysteine) and glycine for 2 weeks | Dietary Supplement: Cysteine (as n-acetylcysteine) and glycine<br>* Cysteine and glycine will be supplemented at doses of 0.81 mmol/kg/d and 1.31 mmol/kg/d for 2 weeks each<br>Dietary Supplement: Cysteine/glycine<br>* Subjects will receive oral dietary amino-acids (cystiene as n-acetylcysteine, and glycine)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glutathione synthesis rates and concentrations | Fractional and absolute synthesis rates of glutathione and its concentrations | 9 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mitochondrial fuel oxidation | Lipolysis, fuel oxidation, and a hyperinsulinemic euglycemic clamp. | Twice over 9 hours of the study on 2 occassions | 
| Rates of fuel kinetics | Measure rate of lipolysis (from infused 13C-palmitate) and recovery of 13CO2 (from infused acetate tracer) | 3 hours | 
| Insulin sensitivity | Measure insulin sensitivity using a hyperglycemic euglycemic clamp | 3 hours | 
| Muscle strength |  | Done once in each 9-hour study | 
| Quality of life by SF36 questionnaire |  | Before and after |