GLUTATHIONE DEFICIENCY IN HIV INFECTION G LUTATHIONE (GSH), a cysteine-containing tripeptide (g-glutamyl-cysteinyl-glycine), is a major cytosolic antioxidant that is present in the cells at millimolar concen- trations. It was first reported by Dröge et al. that human im- munodeficiency virus (HIV)-infected individuals have lower levels of cystine and methionine in plasma and lower levels of GSH in peripheral blood mononuclear cells (PBMCs) (21, 23). Buhl et al. also reported that total and reduced glu- tathione (GSH + GSSG and GSH) levels decrease in plasma and bronchoalveolar lavage fluids in HIV-infected individu- als (10). Folks et al. have suggested that the inflammatory cytokines such as tumor necrosis factor- a play important roles in the progression of acquired immunodeficiency syn- drome (AIDS) (27). Roederer et al. found that N-acetylcys- teine (NAC), the acetylated cysteine that is converted into cysteine required for GSH synthesis, inhibits the cytokine- stimulated replication of HIV and activation of nuclear fac- tor-kB (NF-kB) which controls the transcription of genes for HIV replication (68, 78). Furthermore, they revealed that GSH levels are different in subpopulations of PBMCs by flu- orescence-activated cell sorter (FACS) analysis using mono- chlorobimane and that T cells are subdivided into high-GSH cells and low-GSH cells in healthy individuals. Thus, they found that high-GSH T cells are selectively lost in HIV-in- fected individuals (69). The intracellular GSH levels deter- mined by FACS-measured glutathione-S-bimane fluores- cence (GSB) in T cells decrease during the disease progression of AIDS (79). The suppressive effects of NAC on the activation of NF- kB and HIV replication were con- firmed by other groups (35, 48, 65). Meanwhile, Schreck et al. reported that reactive oxygen species (ROS) serve as in- tracellular messengers for the activation of NF- kB and repli- cation of HIV (75). These studies suggested that oxidative stress caused by elevated inflammatory cytokines and de- creased GSH-dependent antioxidant functions in HIV infec- tion promotes the activation of NF- kB and replication of HIV, resulting in the diseaseprogression associated with the 455 Department of Biological Responses, Institute for Virus Research, Kyoto University, 53 Shogin-Kawaharacho, Sakyo, Kyoto 606-8507, Japan. Forum Review Redox Imbalance and Its Control in HIV Infection HAJIME NAKAMURA, HIROSHI MASUTANI, and JUNJI YODOI ABSTRACT Human immunodeficiency virus (HIV)-infected individuals are suffering from systemic oxidative stress. Re- active oxygen species act as second messengers for the activation of nuclear factor-kB (NF-kB), which aug- ments the replication of HIV. Intracellular levels of glutathione (GSH), a major cytosolic antioxidant, in T cells decrease during the disease progression. Another redox-regulating molecule, thioredoxin (TRX), is also transiently down-regulated in the cells by acute HIV infection. In contrast, plasma levels of TRX are elevated in the late stage of HIV infection. Intracellular GSH and plasma TRX can be biomarkers to predict the prog- nosis of the disease. N-Acetylcysteine (NAC), a prodrug of cysteine that is necessary for GSH synthesis, has been used for HIV infection to prevent the activation of NF-kB and the replication of HIV. NAC shows some beneficial effects for HIV-infected individuals, although the intracellular GSH levels in lymphocytes are not significantly restored. The control of imbalanced redox status by antioxidants may be beneficial for the qual- ity of life in HIV infection even in the era after the effective therapy with protease inhibitors has been applied. Redox control will be an important therapeutic strategy for oxidative stress-associated disorders including HIV infection. Antioxid. Redox Signal. 4, 455–464. ANTIOXIDANTS & REDOX SIGNALING Volume 4, Number 3, 2002 © Mary Ann Liebert, Inc.