Antioxidant therapy for AIDS.

HIV infection is characterized by many immunological, neurological and metabolic abnormalities. The intra and extra cellular redox balance also is severely disturbed in HIV-infected individuals. The tripeptide glutathione (GSH) is the main intracellular defense against oxidative stress and regulates the cellular redox potential. Other antioxidant systems, such as thioredoxin, vitamin C, vitamin E and coenzyme Q also contribute to the antioxidant protection mechanisms of cells. An impressive number of papers has demonstrated decreased GSH levels in blood, lymphocytes or lymphocyte subsets and other tissues in both pediatric and adult HIV-infected people [1±10]. GSH ful®lls important roles in the cell; besides its role in maintaining the cellular redox balance, it is essential for synthesis of DNA precursors, reduces protein disul®des and protects the cell against deleterious in ̄uences of reactive oxygen intermediates (ROI). More speci®cally, essentially all aspects of lymphocyte function depend on suf®cient levels of intracellular GSH (for references, see for instance [3]). It seems therefore logical to try to restore GSH to adequate levels during HIV disease. This notion becomes even more attractive, when one takes into account that a wide variety of antioxidants, including GSH replenishing drugs have been shown to inhibit HIV replication ex vivo [11±13]. Among these compounds, N-acetylcysteine (NAC), sometimes in combination with vitamin C or E, has been the drug of choice. This is not surprising, given the known GSH replenishing properties, low cost and low toxicity of NAC. Several groups have proposed GSH replacement therapy for HIV disease, and recently the ®rst clinical studies have been completed [14±17]. Two sizeable clinical trails have also been completed recently [15,16], one of which is published in this current issue of the European Journal of Clinical Investigation [16]. In addition, a small pilot study of high dose NAC in combination with vitamin C is also published in this issue [17]. During the latter study on 8 patients, the group of Muller et al. used a combination of NAC and vitamin C for 6 days [17]. The aim of the study was to investigate the effect of antioxidant treatment on several immunological parameters in HIV-infected individuals. Although obviously very small in design, this pilot study showed some remarkable results. The short-term treatment with antioxidants decreased HIV RNA in plasma and lead to a remarkable 20±30% increase in CD4‡ lymphocyte count. In addition, GSH levels were increased in CD4‡ T cells and lymphocytes showed enhanced proliferation in a standard mitogenic stimulation assay. The two other reports concern placebo-controlled, double-blind clinical trials performed by the two laboratories that originally reported on the importance of low GSH for the pathogenesis of AIDS [15,16]. The German group led by Wulf Droge reported their ®ndings very recently in the Journal of Molecular Medicine, whereas de Rosa et al., the American group, report their ®ndings in this issue of EJCI. The American trial set out to discover if oral administration of NAC would restore GSH levels in T cells and whole blood of 61 HIV infected subjects (31 in the NAC-arm, 30 in the placebo arm) [16]. This was indeed the case, demonstrating that NAC is bio-available to replenish GSH in HIV-infected individuals. This conclusion differs from earlier reports where bioavailability was estimated to be low [18], however, because as NAC is a GSH prodrug, plasma NAC concentrations are of little relevance for assessment of bio availability. Because the relevant measurements were not done in this previous report, the two reports in this issue of EJCI [16,17] now settle this controversy and show that NAC is functionally bio available in HIV infected patients. The American trial did not investigate virological or immunological parameters, but did look at 2±3 years survival, which increased dramatically in patients who took NAC. In contrast, the German trial investigated several metabolic and immunological parameters, without investigating GSH levels in blood or T cells [15]. This trial