Antioxidant therapy for AIDS

HIV infection is characterized by many immunological,neurological and metabolic abnormalities. The intra andextra cellular redox balance also is severely disturbed inHIV-infected individuals. The tripeptide glutathione(GSH) is the main intracellular defense against oxidativestress and regulates the cellular redox potential. Otherantioxidant systems, such as thioredoxin, vitamin C, vita-min E and coenzyme Q also contribute to the antioxidantprotection mechanisms of cells. An impressive number ofpapers has demonstrated decreased GSH levels in blood,lymphocytes or lymphocyte subsets and other tissues inboth pediatric and adult HIV-infected people [1–10].GSH fullls important roles in the cell; besides its role inmaintaining the cellular redox balance, it is essential forsynthesis of DNA precursors, reduces protein disuldesand protects the cell against deleterious inuences ofreactive oxygen intermediates (ROI). More specically,essentially all aspects of lymphocyte function depend onsufcient levels of intracellular GSH (for references, see forinstance [3]).It seems therefore logical to try to restore GSH toadequate levels during HIV disease. This notion becomeseven more attractive, when one takes into account that awide variety of antioxidants, including GSH replenishingdrugs 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, giventhe known GSH replenishing properties, low cost and lowtoxicity of NAC.Several groups haveproposed GSH replacement therapyfor HIV disease, and recently the rst clinical studies havebeen completed [14–17]. Two sizeable clinical trails havealso been completed recently [15,16], one of which ispublished in this current issue of the European Journal ofClinical Investigation [16]. In addition, a small pilot study ofhigh dose NAC in combination with vitamin C is alsopublished in this issue [17].During the latter study on 8 patients, the group ofMuller et al. used a combination of NAC and vitamin Cfor 6days [17]. The aim of the study was to investigate theeffect of antioxidant treatment on several immunologicalparameters in HIV-infected individuals. Althoughobviously very small in design, this pilot study showedsome remarkable results. The short-term treatment withantioxidants decreased HIV RNA in plasma and lead to aremarkable 20–30% increase in CD4⁄ lymphocyte count.In addition, GSH levels were increased in CD4⁄ T cellsand lymphocytes showed enhanced proliferation in a stan-dard mitogenic stimulation assay.The two other reports concern placebo-controlled,double-blind clinical trials performed by the two labora-tories that originally reported on the importance of lowGSH for the pathogenesis of AIDS [15,16]. The Germangroup led by Wulf Droge reported their ndings veryrecently in the Journal of Molecular Medicine, whereas deRosa et al., the American group, report their ndings in thisissue of EJCI. The American trial set out to discover if oraladministration of NAC would restore GSH levels in T cellsand whole blood of 61 HIV infected subjects (31 in theNAC-arm, 30 in the placebo arm) [16]. This was indeedthe case, demonstrating that NAC is bio-available toreplenish GSH in HIV-infected individuals. This conclu-sion differs from earlier reports where bioavailability wasestimated to be low [18], however, because as NAC is aGSH prodrug, plasma NAC concentrations are of littlerelevance for assessment of bio availability. Because therelevant measurements were not done in this previousreport, the two reports in this issue of EJCI [16,17] nowsettle this controversy and show that NAC is functionallybio available in HIV infected patients.The American trial did not investigate virological orimmunological parameters, but did look at 2–3 yearssurvival, which increased dramatically in patients whotook NAC. In contrast, the German trial investigatedseveral metabolic and immunological parameters, withoutinvestigating GSH levels in blood or T cells [15]. This trial