Ghezzi of plasma cysteine. 67 The reasons for this are not clear, but AIDS patients have a deficit in the enzyme gamma cystathionase, which synthesizes cysteine from the methionine. 10 Later research showed that AIDS causes a decrease in intracellular GSH in CD4 T cells, and that low GSH is associated with decreased survival. 68 The lower GSH levels in AIDS patients could have various consequences. GSH depletion, at least in vitro, augments HIV replication, 69 while its precursor NAC blocks the stimulatory effect of tumor necrosis factor on HIV replication. 70 Furthermore, the neurotoxic effect of HIV proteins Tat and gp120 is associated with oxidative stress and antagonized by NAC. 71, 72 Example 3: bacterial infectionstuberculosis Mycobacterium tuberculosis is an intracellular pathogen that grows in the phagosomes, where it is protected from immune system effectors such as antibodies and T lymphocytes. Although the literature showing that GSH levels are lower in patients with tuberculosis dates back to the 1950s, it was not until the research of Venketaraman and colleagues that the effect of GSH on M. tuberculosis infection was studied in depth. Using a mouse macrophage cell line, the authors show that IFN-gamma and endotoxin increase both nitric oxide (NO) production and bactericidal activity; the paralleled decrease in GSH suggests that GSH reacts with NO to form S-nitrosoglutathione (GSNO). Under these experimental conditions, GSH depletion with BSO inhibited the microbicidal activity of macrophages while its precursor NAC increased intracellular killing of mycobacteria also from human macrophages, which are normally not very effective in killing mycobacteria. 73, 74 Other investigators have shown that the trans-sulfuration pathway, which converts methionine into cysteine and has a key role in maintaining cysteine, and hence GSH levels, is essential for mycobacterial killing. 75 In that study, it was found that not only are trans-sulfuration pathway enzymes increased in human monocytes as a response to mycobacteria, but their inhibitor propargylglycine lowered GSH levels and inhibited clearance of mycobacteria and phagolysosome fusion, while NAC increased them. 75 Similar results were obtained in whole human blood cultures. 76 In vitro, both GSH and GSNO have direct bactericidal activity against these pathogens. 77 This complex picture has been nicely reviewed by Connell and Venkataraman 78 and is summarized in Figure 5 . Depletion of GSH (by BSO or diethylmaleate) also inhibits macrophage leishmanicidal activity, as well as NO production, while the GSH precursor GSH-ethyl ester restores them, 79 suggesting that the requirement for the GSH/NO pathway might be a common feature of resistance to intracellular pathogens.