N-acetylcysteine replenishes glutathione in HIV infection.

BACKGROUND: Glutathione (GSH) deficiency is common in HIV-infected individuals and is associated with impaired T cell function and impaired survival. N-acetylcysteine (NAC) is used to replenish GSH that has been depleted by acetaminophen overdose. Studies here test oral administration of NAC for safe and effective GSH replenishment in HIV infection. DESIGN: Oral NAC administration in a randomized, 8-week double-blind, placebo-controlled trial followed by optional open-label drug for up to 24 weeks. SUBJECTS: HIV-infected, low GSH, CD4 T cells < 500 micro L(-1), no active opportunistic infections or other debilitation; n = 81. Study conducted prior to introduction of protease inhibitors. RESULTS: Whole blood GSH levels in NAC arm subjects significantly increased from 0.88 mM to 0.98 mM, bringing GSH levels in NAC-treated subjects to 89% of uninfected controls (P = 0.03). Baseline GSH levels in the placebo group (0.91) remained essentially the same during the 8 week placebo-controlled trial. T cell GSH, adjusted for CD4 T cell count and beta2-microglobulin levels, also increased in the NAC-treated subjects (P = 0.04). Adverse effects were minimal and not significantly associated with NAC ingestion. CONCLUSION: NAC treatment for 8 weeks safely replenishes whole blood GSH and T cell GSH in HIV-infected individuals. Thus, NAC offers useful adjunct therapy to increase protection against oxidative stress, improve immune system function and increase detoxification of acetaminophen and other drugs. These findings suggest that NAC therapy could be valuable in other clinical situations in which GSH deficiency or oxidative stress plays a role in disease pathology, e.g. rheumatoid arthritis, Parkinson's disease, hepatitis, liver cirrhosis, septic shock and diabetes.

Glutathione deficiency is associated with impaired survival in HIV disease.

Glutathione (GSH), a cysteine-containing tripeptide, is essential for the viability and function of virtually all cells. In vitro studies showing that low GSH levels both promote HIV expression and impair T cell function suggested a link between GSH depletion and HIV disease progression. Clinical studies presented here directly demonstrate that low GSH levels predict poor survival in otherwise indistinguishable HIV-infected subjects. Specifically, we show that GSH deficiency in CD4 T cells from such subjects is associated with markedly decreased survival 2-3 years after baseline data collection (Kaplan-Meier and logistic regression analyses, P < 0.0001 for both analyses). This finding, supported by evidence demonstrating that oral administration of the GSH prodrug N-acetylcysteine replenishes GSH in these subjects and suggesting that N-acetylcysteine administration can improve their survival, establishes GSH deficiency as a key determinant of survival in HIV disease. Further, it argues strongly that the unnecessary or excessive use of acetaminophen, alcohol, or other drugs known to deplete GSH should be avoided by HIV-infected individuals.

Elevation of plasma thioredoxin levels in HIV-infected individuals.

Thioredoxin (Trx), a ubiquitous protein intimately involved in redox and protein disulfide reductions, has been shown to be released from cells and to have cytokine-like activities. In addition, Trx has been implicated in the redox regulation of immunological responses and shown to be deficient in tissues from AIDS patients. In studies presented here, plasma Trx levels were measured by ELISA in plasma samples from HIV-infected individuals (n = 136) and HIV-negative controls (n = 47). To account for the release of Trx into plasma due to hemolysis, the Trx measurements were corrected according to the level of hemoglobin in the plasma sample. Data presented show that, in contrast to tissue Trx levels, corrected plasma Trx levels are significantly higher in HIV-infected individuals than in controls (P < 0.0001). Furthermore, approximately 25% of the HIV-infected individuals studied have plasma Trx levels greater than the highest levels found in controls (37 ng/ml). Detailed multiparameter FACS analysis of peripheral blood mononuclear cells (PBMC) from the infected individuals demonstrates that those with higher plasma Trx levels (37 ng/ml or greater) tend to have lower overall CD4 counts. In addition, increases in plasma Trx levels correlate with decreases in monochlorobimane staining (indicative of lower intracellular glutathione levels in PBMC) and with changes in surface antigen expression (CD62L, CD38 and CD20) that occur in the later stages of HIV infection. These correlations suggest that elevation of plasma Trx levels may be an important component of advanced HIV disease, perhaps related to the oxidative stress that often occurs at this stage.