1. Vaandrager GJ, Bruining GJ, Veenhof FJ, Drayer NM. Incidence



childhood diabetes in the Netherlands: a decrease from north to south over North-Western Europe? Diabetologia 1984; 27: 203-06. 2. LaPorte RE, Tajima N, Akerblom HK, et al. Geographic differences in the risk of insulin-dependent diabetes mellitus: the importance of registries. Diabetes Care 1985; 8 (suppl 1): 101-07. 3. Green A, King HOM, LaPorte RE. Workshop on diabetes registers: the role of IDDM registers in diabetes research and care. In: Serrano Rios M, Lefébvre JP, eds. Diabetes, 1985. Amsterdam: Elsevier, 1986: 443-48. 4. Rothman KJ. Modern epidemiology. Boston: Little, Brown and

Company, 1986: 41-44. 5. Bishop YMM, Fienberg SE, Holland PW. Discrete multivariate analysis: theory and practice. Cambridge, Massachusetts: MIT Press, 1974: 229-37. 6. Holford TR. The

and of survivorship using log linear models. Biometrics 1980; 36: 299-305. 7. Schober E, Fnsch H. Incidence of childhood diabetes mellitus in Austria 1979-1984. Acta Paediatr Scand 1988; 77: 299-302. 8. Soltész G, Madácsy L, Békefi D, Dankó I, the Hungarian Childhood Diabetes Epidemiology Group. Rising incidence of Type 1 diabetes in Hungarian children (1978-1987). Diabetic Med 1990; 7: 111-14. 9. Laron Z, Karp M, Modan M. The incidence of IDDM in Israeli children and adolescents 0-20 years of age: a retrospective study, 1975-1980. Diabetes Care 1985; 8 (suppl 1): 24-28. 10. Joner G, Søvik O. Increasing incidence of diabetes mellitus in Norwegian children 0-14 years of age 1973-1982. Diabetologia 1989; 32: 79-83. 11. Rewers M, LaPorte RE, Walczak M, Dmochowski K, Bogaczynska E. Apparent epidemic of insulin-dependent diabetes mellitus in Midwestern Poland. Diabetologia 1987; 36: 106-13. 12. Bingley PJ, Gale EAM. Incidence of insulin dependent diabetes in England: a study in the Oxford region, 1985-6. Br Med J 1989; 298: 558-60. 13. Lestradet H, Besse J. Prévalence et incidence du diabète juvénile insulinodépendant en France. Diabète Métab 1977; 3: 29-34. 14. Hours M, Fabry J, Siemiatycki J, Francois R. Diabète insulinodépendant juvénile: etute descriptive dans le départment du Rhône. Rev Epidémiol et Santé Public 1984; 32: 107-12. 15. Levy-Marchal C, Papoz L, de Beaufort C, et al. Incidence of juvenile Type 1 (insulin-dependent) diabetes mellitus in France. Diabetologia 1990; 33: 465-69.

analysis of rates

Christy M, Green A, Christau B, Kromann H, Nerup J. Epidemiologic studies of insulin dependent diabetes mellitus. Diabetes Care 1979; 2:

127-30. 17. de Beaufort

CE, Michel G, Glaesener G. The incidence of type 1 (insulin-dependent) diabetes mellitus in subjects aged 0-19 years in Luxembourg: a retrospective study from 1977 to 1986. Diabetologia 1988; 31: 758-61.

18. Akerblom HK, Reunanen A. The epidemiology of insulin-dependent diabetes (IDDM) in Finland and Northern Europe. Diabetes Care 1985; 8 (suppl 1): 10-16. 19. Diabetes Epidemiology Research International Group. Geographic patterns of childhood insulin-dependent diabetes mellitus. Diabetes

1988, 37: 1113-19. AV, Helgason T, Jonasson MR, Danielsen R. Childhood

20. Thorsson

diabetes in Iceland in the last two decades. Presentation at International Symposium on Epidemiology and Etiology of IDDM in the Young,

France, May 1991. A, Gale EAM. The aetiology and pathogenesis of insulindependent diabetes: an epidemiological perspective. In: Fuller J, Williams R, Papoz L, eds. Diabetes in Europe. London: John Libby (in press). 22. Nystrom L, Dahlquist G, Rewers M, Wall S. The Swedish Childhood Diabetes Study. An analysis of the temporal variation in diabetes 21. Green

incidence 1978-1987. Int J Epidemiol 1990; 19: 141-46. 23. Metcalfe MA, Baum JD. Incidence of insulin dependent diabetes in children aged under 15 years in the British Isles during 1988. Br Med J 1991; 302: 443-47. 24. Kalits I, Podar T. Incidence and prevalence of Type 1 (insulindependent) diabetes in Estonia m 1988. Diabetologia 1990; 33: 346-49. 25. Shubnikov E, Podar T, Tuomilehto J. Incidence of childhood IDDM in the city of Novosibirsk during 1985-1987. Diabetes 1991; 40 (suppl 1): abstr 1253. 26. Tuomilehto-Wolf E, Tuomilehto J, Cepaitis Z, Lounamaa R, DIME Study Group. New susceptibility haplotype for type 1 diabetes. Lancet 1989; ii: 299-302. 27. Carcassi C, Trucco G, Trucco M, Contu L. An HLA-DR2 haplotype confers susceptibility to Type 1 diabetes in Sardinia. Diabetes 1990; 39(suppl 1): abstr 60. 28. Barnett AH, Eff C, Leslie RDG, Pyke DA. Diabetes in identical twins: a study of 200 pairs. Diabetologia 1981; 20: 87-93. 29. Bingley PJ, Gale EAM. Rising incidence of IDDM in Europe. Diabetes

Care 1989; 12: 289-95.

REVIEW ARTICLE Glutathione deficiency and human immunodeficiency virus infection

Introduction Glutathione (GSH), the main intracellular defence

against oxidative stress, is decreased in plasma, lung epithelial-lining fluid, and T lymphocytes in individuals infected with human immunodeficiency virus (HIV). This

deficiency may potentiate HIV replication and accelerate disease progression, especially in individuals with increased concentrations of inflammatory cytokines because such cytokines stimulate HIV replication more efficiently in GSH-depleted cells. GSH deficiency also contributes to the overall depression of immune functions. Drugs that replenish GSH, such as N-acetylcysteine, counteract oxidative stress and inhibit HIV transcription and replication in models of


and latent HIV infection.

Here we review the role of GSH in HIV infection and the potential for counteracting GSH deficiency with drugs.

Metabolism and functions of GSH is


cysteine-containing tripeptide (y-glutamylcysteinyl-glycine) that is found in eukaryotic cells at a

millimolar concentrations. Its cellular functions include aminoacid transport, acting as a cofactor in enzymic reactions, and maintenance of protein sulphydryl redox status. Furthermore, GSH is a defence against electrophylic xenobiotics and intracellular oxidants (free radicals, reactive oxygen intermediates).1 Therefore, GSH is also a regulator of cellular redox potential. Synthesis and degradation of ADDRESS Department of Genetics, Beckman Center B007, Stanford University School of Medicine, Stanford, California 94305, USA (F J. T. Staal, MSc, S. W. Ela, PhD, M. Roederer, PhD, M T. Anderson, PhD, Prof L A. Herzenberg, PhD, Prof L A. Herzenberg, PhD). Correspondence to Prof Leonard A. Herzenberg.


of CD4 and CDS T cells containing high and low intracellular concentrations of GSH,.10 Whereas the ratio of these two cell types varies considerably from individual to individual, the GSH concentrations of each type are highly conserved among individuals. High-GSH T cells are depleted from the CD4 and CDS T cell subpopulations of HIV-infected individuals, even in the symptom-free stages of the disease.9 The selective loss of high-GSH T cells results in lower median GSH concentrations in the T cells of HIV-infected individuals. For example, in patients with

Fig 1-GSH metabolism. Simplified representation of the major biosynthetic pathway and protective functions (detoxifying free radicals, peroxides, and xenobiotics) of GSH. X, xenobiotic, GSSG, GSH disulphide Enzyme names are


are part of the y-glutamyl cycle in which GSH is synthesised by the action of two ATP-consuming enzymes: y-glutamylcysteine synthetase and GSH synthetase (fig 1). Reduced GSH can be oxidised to GSH disulphide either non-enzymically or through the activity of GSH peroxidase (fig 1). Under normal conditions, GSH disulphide can be reduced by GSH disulphide reductase to regenerate GSH. Adequate concentrations of GSH are required for mixed lymphocyte reactionsT-cell proliferationT and B cell differentiation,3 cytotoxic T-cell activity, and natural killer cell activity.4 Decreasing GSH by 10 to 40% can inhibit completely T-cell activation in vitro.5 Thus, an intracellular GSH deficiency in lymphocytes has profound effects on


immune functions.


glutathione concentrations in


infection Several groups have demonstrated depleted GSH in the tissues of HIV-infected individuals (fig 2). Eck and colleagues6 were the first to show that HIV-infected individuals have decreased concentrations of acid-soluble thiols (cysteine and GSH) in their plasma and in cell lysates of peripheral blood morlonuclear cells (PBMCs).6 These changes were found in symptom-free individuals, indicating that they were not the consequence of a wasting syndrome. The same patients also had increased plasma glutamate concentrations, which inhibit the cystine uptake needed for GSH synthesis. Buhl et aF confirmed the lower plasma GSH concentrations and, in addition, showed that GSH concentrations were decreased in lung epithelial-lining fluids of 14 symptom-free HIV-infected individuals. This

finding indicates that HIV infection is accompanied by a systemic deficiency of extracellular GSH. HIV-infected children also have plasma and whole-blood GSH deficiencies.8 We have examined intracellular GSH concentrations in PBMC subsets (CD4 and CDS T cells, B cells, and monocytes) from 134 HIV-infected individuals in different stages of HIV-related disease.9 With a fluorescenceactivated-cell-sorter-based flow cytometric method we showed that in healthy controls there are two distinct types

symptomatic acquired immunodeficiency syndrome (AIDS), GSH concentrations in CDS and CD4 T cells are 62 and 63%, respectively, of those found in seronegative controls. Other PBMC subsets (eg, B cells and monocytes) do not show significant decreases in GSH concentrations. However, some changes in GSH regulation seem to occur in B lymphocytes. B-cell GSH concentrations vary considerably more among HIV-infected than among healthy individuals. Furthermore, in HIV-infected individuals, but not in uninfected controls, GSH concentrations correlate with increased expression of the pan B-cell surface antigen CD20.11 Further proof of the early depletion of GSH after HIV infection came from a study which showed that thiol depletion occurred soon after infection (within one week) in a primate model for AID S in which macaques were infected with simian immunodeficiency virus." The same study also found alterations in serum cysteine and glutamate concentrations, similar to those found in human beings, indicating that thiol depletion may be a general consequence of simian immunodeficiency virus and HIV infection. Glutathione concentrations and regulation of HIV transcription and replication in vitro

Inflammatory cytokines (interleukins 1 and 6, and necrosis factor alpha) and phorbol esters can stimulate HIV production in vitro." N-acetylcysteine, which replenishes and enhances intracellular GSH, inhibits cytokine-stimulated HIV replication in acutely infected Molt4 T cells/4 chronically infected cells/5 and in normal tumour

PMBCs infected in vitro. 14 GSH and GSH esters also block cytokine-stimulated HIV transcription.16 The mechanism for thiol regulation of HIV activation can largely be explained by the influence of thiols on the nuclear factor KB (NF-KB) transcription factor. NF-xB is a nuclear factor that binds to the enhancer of the K light chain17 and greatly increases HIV transcription and replication.18 Stimulation of NF-xB with tumour necrosis factor alpha with or without phorbol myristate acetate, which can generate intracellular oxidants,19 is effectively inhibited by N-acetylcysteine .20 Moreover, oxidants (eg, H2û2) activate NF-KB and HIV transcription directly and Nacetylcysteine blocks this activation.21 By contrast, diamide pretreatment oxidises intracellular GSH and facilitates cytokine-stimulated HIV-directed transcription.2° Thus, transduction of the NF-KB (and HIV) activation signal is more likely or potentiated when thiol concentrations are low and is less likely or inhibited when thiols are maintained at high concentrations-ie, redox mechanisms regulate HIV activation. We do not know if N-acetylcysteine acts to replete GSH concentrations or to scavenge oxidants directly. Under certain conditions, N-acetylcysteine is a direct scavenger of reactive oxygen intermediates (ROIs).22 When de-novo GSH synthesis is inhibited by buthionine sulphoximine (an irreversible inhibitor of


rercent or

Glutathione deficiency and human immunodeficiency virus infection.

909 REFERENCES 1. Vaandrager GJ, Bruining GJ, Veenhof FJ, Drayer NM. Incidence 16. of childhood diabetes in the Netherlands: a decrease from nort...
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