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.

Study Overview

• Status: Completed
• Conditions: HIV Infection; Erythrocyte Glutathione Deficiency
• Intervention / Treatment: Dietary supplement: Cysteine (as n-acetylcysteine) and glycine; Dietary supplement: Cysteine/glycine

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor GCRC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

(1) HIV infected patients with GSH deficiency

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cysteine/glycine; 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; Cysteine and glycine will be supplemented at doses of 0.81 mmol/kg/d and 1.31 mmol/kg/d for 2 weeks each; Dietary supplement: Cysteine/glycine; Subjects will receive oral dietary amino-acids (cystiene as n-acetylcysteine, and glycine)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Baylor College of Medicine

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Actual): September 1, 2011
• Study Completion (Actual): September 1, 2011

Study Registration Dates

• First Submitted: March 30, 2011
• First Submitted That Met QC Criteria: May 17, 2011
• First Posted (Estimate): May 18, 2011

Study Record Updates

• Last Update Posted (Estimate): February 7, 2013
• Last Update Submitted That Met QC Criteria: February 5, 2013
• Last Verified: February 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Glycine Agents; Acetylcysteine; N-monoacetylcystine; Glycine
• Other Study ID Numbers: HIV and glutathione