Glutathione inhibits HIV replication by acting at late stages of the virus life cycle
Palamara AT, Perno CF, Aquaro S, Bue MC, Dini L, Garaci E.
[AIDS Res Hum Retroviruses 1996 Nov 1;12(16):1537-41] We investigated the effect of glutathione on the replication of human immunodeficiency virus (HIV) in chronically infected macrophages, a known reservoir of the virus in the body.... exogenous GSH strongly suppresses the production of p24gag protein as well as the virus infectivity. This is related to a dramatic decrease in both budding and release of virus particles from chronically infected cells (either macrophages or lymphocytes)... Overall data suggest that GSH can interfere with late stages of virus replication. ...the suppression of virus replication by GSH is related to the selective inhibition of envelope glycoproteins. These results suggest a potential role of GSH in combination with other antivirals in the treatment of virus-related diseases.

Intracellular glutathione as a possible direct blocker of HIV type 1 reverse transcription
Kameoka M, Okada Y, Tobiume M, Kimura T, Ikuta K. [AIDS Res Hum Retroviruses. 1996 Nov 20;12(17):1635-8.] In AIDS patients, chronic inflammation and elevated levels of cytokines seem to be associated with reduced levels of glutathione (GSH). GSH has been proposed to inhibit the activation of NF-kB, which results in the inhibition of HIV-1 replication. Here, we show the evidence that GSH and N-acetylcysteine...could inhibit the reverse transcriptase (RT) process of HIV-1.

Glutathione and N-acetylcysteine suppression of human immunodeficiency virus replication in human monocyte /macrophages in vitro Ho WZ, Douglas SD. [AIDS Res Hum Retroviruses 1992 Jul;8(7):1249-53] The inhibitory effects of GSH and NAC were concentration dependent. This anti-HIV-1 effect persisted in these cultures for at least 35 days without evidence of significant increase in HIV-1 expression. Thus, a single pulse exposure of HIV-1-infected monocyte/macrophages with GSH or NAC led to a sustained, concentration-dependent decrease in HIV-1 p24 antigen levels, as well as, reverse transcriptase activity without producing detectable cellular toxicity in monocyte/macrophages.

Cysteine, glutathione (GSH) and zinc and copper ions together are effective, natural, intracellular inhibitors of (AIDS) viruses
Sprietsma JE.
[Med Hypotheses. 1999 Jun;52(6):529-38. Review] Comment in: Med Hypotheses. 2000 Nov;55(5):456-7. The way in which the right amount of cysteine, glutathione (GSH), and copper and zinc ions made available in the right place at the right time and in the right form can prevent an unchecked multiplication of (AIDS) viruses in a more passive or active way forms the basis for the AIDS zinc-deficiency hypothesis (A-Z hypothesis) presented in this article. Zinc and copper ions that remain available in sufficient amounts via cysteine/GSH are effective natural inhibitors/combaters of (AIDS) viruses and thereby prevent the development of chronic virus diseases that can lead to AIDS, autoimmune diseases, (food) allergies and/or cancer. A safe, relatively inexpensive and extensively tested medicine such as N-acetylcysteine (NAC) can help in supplying extra cysteine.

Glutathione deficiency is associated with impaired survival in HIV disease
Herzenberg LA, De Rosa SC, Dubs JG, Roederer M, Anderson MT, Ela SW, Deresinski SC, Herzenberg LA. In vitro studies showing that low GSH levels both promote HIV expression and impair T cell function suggested a link between GSH depletion and HIV disease progression. Clinical studies presented here directly demonstrate that low GSH levels predict poor survival in otherwise indistinguishable HIV-infected subjects. Specifically, we show that GSH deficiency in CD4 T cells from such subjects is associated with markedly decreased survival 2-3 years after baseline data collection. This finding ...establishes GSH deficiency as a key determinant of survival in HIV disease... the unnecessary or excessive use of acetaminophen, alcohol, or other drugs known to deplete GSH should be avoided by HIV-infected individuals.
Publication Types: Clinical Trial
Randomized Controlled Trial

Low serum thiol levels predict shorter times-to-death among HIV-infected injecting drug users
Michael Marmor, Philip Alcabes, Stephen Titus, Krystyna Frenkel, Keith Krasinski, Arthur Penn and Ronald W. Pero [AIDS 1997, 11:13891393] Among HIV-infected persons, low serum thiols, especially in concert with a history of AIDS, predict mortality risk. These findings support the hypothesis that oxidative stress is critical to the pathogenesis of HIV infection.

Oral supplementation with whey proteins increases plasma glutathione levels of HIV-infected patients
Micke P, Beeh KM, Schlaak JF, Buhl R. [Eur J Clin Invest. 2001 Feb;31(2):171-8.] HIV infection is characterized by an enhanced oxidant burden and a systemic deficiency of the tripeptide glutathione (GSH), a major antioxidant......different strategies to supplement cysteine supply have been suggested to increase glutathione levels in HIV-infected individuals...... to evaluate the effect of oral supplementation with two different cysteine-rich whey protein formulas on plasma GSH levels and parameters of oxidative stress and immune status in HIV-infected patients.....In glutathione-deficient patients with advanced HIV-infection, short-term oral supplementation with whey proteins increases plasma glutathione levels. A long-term clinical trial is clearly warranted to see if this "biochemical efficacy" of whey proteins translates into a more favourable course of the disease.

Effects of long-term supplementation with whey proteins on plasma glutathione levels of HIV-infected patients
Micke P, Beeh KM, Buhl R. [Eur J Nutr 2002 Feb;41(1):12-8] HIV infection is characterized by an enhanced oxidant burden and a systemic deficiency of the tripeptide glutathione (GSH), a major antioxidant. Whey proteins are rich in cysteine as well as in GSH precursor peptides. In order to evaluate the effects of whey supplementation on plasma GSH levels, HIV-infected patients were treated with whey proteins for a period of six months. Supplementation with whey proteins persistently increased plasma glutathione levels in patients with advanced HIV-infection.

Nutriceutical Modulation Of Glutathione With A Humanized Native Milk Serum Protein Isolate: Application In AIDS And Cancer. (Go to main page to view and order S. Baruchel, G. Viau, R. Olivier, G. Bounous, M.A. Wainberg [Oxidative Stress in Cancer, AIDS, and Neurodegenerative Diseases V Luc Montagnier et al., (Ed.) Marcel Dekker Inc., New York: 447-461, 1998 . ABSTRACT V] The biological activity of the proteins isolated from cow's milk in the whey protein isolate depends on the preservation of those labile proteins which share with the predominant human milk proteins the same extremely rare glutathione (GSH)-promoting components. In a pilot study, this type of whey protein concentrate was found to be well tolerated in children with AIDS and wasting syndrome and was found associated with an improvement of the nutritional status of the patient. Moreover, the GSH promoting activity on the peripheral blood lymphocyte of this protein concentrate was validated in patients with initial low GSH levels.

Immuno-Enhancing Properties Of Undenatured Milk Serum Protein Isolate In HIV Patients.
G. Bounous
[International Diary Federation: WHEY: 293-305, 1998] ABSTRACT When GSH is depleted, as in the lymphocytes of mice during the immune response or in the lymphocyte of AIDS patients, the cysteine delivery system in a patented whey potein isolate produces a substantial increase in cellular GSH up to, but not above, normal values. Preliminary data in AIDS patients demonstrate that this is associated with major improvements in health. These clinical data and the in vitro demonstration that whey potein isolate inhibits the HIV virus while increasing GSH synthesis strongly suggest that an antagonistic relation exists between the virus and cellular GSH. Unlike specific antiretroviral drugs which may induce mutation, hence resistance of the virus to therapy, the normalization of the lymphocyte glutathione levels and redox status through a cysteine delivery system represents a totally different approach by which the natural cellular defense system is boosted. It is conceivable that GSH restoration by whey protein could prevent to a certain extent the adverse effect of AZT.

L-Glutathione decreases replication of HIV and other viruses - increases CD8 counts and function
Chen P. and Schwartz D
[Int Conf AIDS 1993 (abstract PO-A13-0248)] Depletion of intracellular GSH (Glutathione)....decreases the proportion of CD8+ cells (i.e. increases the CD4/CD8 ratio) ...and inhibits ....cytotoxic T lymphocyte (CTL) activity. Low levels of Glutathione in the cells not only decreases the total CD8 counts but decrease the functioning of the CD8 Cytotoxic T cells, that is, their ability to control the viral infections by killing the virus infected cells. Research also shows that increasing Glutathione levels reduces Tumor Necrosis Factor (TNF). High TNF levels have been linked to wasting syndrome and increased viral replication. Taking Glutathione supplements may not be an effective way to increase GSH levels due to poor assimilation.

Improvement of immune functions in HIV infection by sulfur supplementation: Two randomized trials.
Breitkreutz R, Pittack N and others.
[J Mol Med 2000;78(1):55-62]. "Our findings suggest that the impairment of immunological functions in HIV+ patients results at least partly from cysteine deficiency.
Because immune reconstitution is a widely accepted aim of HIV treatment, N-acetyl-cysteine [NAC] treatment may be recommended for patients with and without antiretroviral therapy. Our previous report on the massive loss of sulfur in HIV-infected subjects and the present demonstration of the immunoreconstituting effect of cysteine supplementation indicate that the HIV-induced cysteine depletion is a novel mechanism by which a virus destroys the immune defense of the host and escapes immune elimination."

Whey proteins as a food supplement in HIV-seropositive individuals.
Bounous G, Baruchel S, Falutz J, Gold P. [Clin Invest Med. 1993 Jun;16(3):204-9.] Preliminary data indicate that, in patients who maintain an adequate total caloric intake, the addition of "bioactive" whey protein concentrate as a significant portion of total protein intake increases body weight and shows elevation of glutathione (GSH) content of mononuclear cells toward normal levels.


Stanford NAC Study: Glutathione Level Predicts Survival
Author: John S. James
[AIDS Treatment News; Issue: 266 03/07/97] A small randomized controlled trial of oral N-acetylcysteine(NAC) was run in San Francisco in 1993 and 1994. A report from this study was published in the PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA (1); it was also presented at a major immunology conference in San Francisco on February 22, receiving television and newspaper coverage. For persons with a CD4 count under 200, an abnormally low level of glutathione -- inside CD4 T-cells in the blood --was remarkably predictive of poor survival. (Glutathione is the major defense of those cells against oxidative stress.) Oral NAC helped to replenish low glutathione in blood cells. These findings alone do not prove that NAC is beneficial...followup studies showed that persons who were given or chose to take NAC during the trial had considerably better survival than similar subjects who did not take NAC.

N- acetylcysteine replenishes glutathione in HIV infection
De Rosa SC, Zaretsky MD, Dubs JG, and others. [Eur J Clin Invest 2000 Oct;30(10):915-29.] Comment in: Eur J Clin Invest. 2000 Oct;30(10):841-2. Studies here test oral administration of NAC for safe and effective GSH replenishment in HIV infection. NAC offers useful adjunct therapy to increase protection against oxidative stress, improve immune system function and increase detoxification of acetaminophen and other drugs. These findings suggest that NAC therapy could be valuable in other clinical situations in which GSH deficiency or oxidative stress plays a role in disease pathology.
Publication Types: Clinical Trial
Randomized Controlled Trial

Glutathione depletion in HIV-infected patients: role of cysteine deficiency and effect of oral N-acetylcysteine
de Quay B, Malinverni R, Lauterburg BH.
[AIDS 1992 Aug;6(8):815-9] To determine whether a single oral dose of N-acetylcysteine corrects the deficiency of cysteine and glutathione in plasma and mononuclear cells of HIV-infected patients. A single oral dose of N-acetylcysteine increased the concentration of cysteine in plasma and mononuclear cells of HIV-infected patients. Oral N-acetylcysteine transiently increases the concentrations of cysteine and glutathione in mononuclear cells of patients with HIV infection. A sustained increase in intracellular cysteine may be necessary to normalize intracellular glutathione. This may be accomplished by repeat administration of N-acetylcysteine.

Cysteine and glutathione deficiency in HIV-infected patients. The basis for treatment with N-acetyl-cysteine
Droge W. [Pharmacology. 1993;46(2):61-5.] Clinical studies and complementary laboratory investigations suggest that the deterioration of the immune system in HIV-infected patients may be the consequence of a virus-induced cysteine deficiency. HIV-infected persons at all stages of the disease have, on the average, decreased plasma cystine and cysteine and decreased intracellular glutathione levels. Cysteine levels also decrease in rhesus macaques within 1 to 2 weeks after infection with SIV(mac). HIV-infected persons and SIV-infected macaques also have, on the average, markedly increased plasma glutamate levels, which aggravate the cysteine deficiency by inhibiting the membrane transport of cystine. Even moderately increased extracellular glutamate levels as they are found in HIV-infected persons cause a profound decrease of intracellular cyst(e)ine levels. A correlation between individual T4+ cell counts (but not T8+ cell counts) and individual cystine and glutamate levels has been found not only in HIV-infected persons but also in healthy individuals, indicating that the linkage between cysteine supply and immune system is demonstrable even in the absence of the virus. There is suggestive evidence that the HIV-induced cysteine deficiency is not only responsible for the 'cellular dysfunction' but also for the abnormal activation which is exemplified by the lymphadenopathy syndrome and abnormal antibody production. We have... suggested that N-acetyl-cysteine (NAC) may be considered for the replenishment of cysteine and glutathione levels in HIV-infected persons, since NAC is a well-established and safe drug with well-documented pharmacokinetics.

HIV-induced cysteine deficiency and T-cell dysfunction--a rationale for treatment with N-acetylcysteine

Droge W, Eck HP, Mihm S. [Immunol Today. 1992 Jun;13(6):211-4.] Markedly decreased plasma cystine and cysteine concentrations have been found in HIV-infected patients at all stages of the disease and in SIV-infected rhesus macaques. The elevated glutamate levels found in the same patients aggravate the cysteine deficiency by inhibiting the membrane transport activity for cystine. The intact immune system appears to require a delicate balance between pro-oxidant and antioxidant conditions, maintained by a limited and well-regulated supply of cysteine. This balance is obviously disturbed in HIV infection and may contribute to the pathogenesis of AIDS.

Role of cysteine and glutathione in HIV infection and cancer cachexia: therapeutic intervention with N-acetylcysteine

Droge W. et al.
[Adv Pharm 38: 581-600, 1997.]

Nutrition and HIV
Lichtenstein BS. [STEP Perspect. 1995 Spring;7(1):2-5.] AIDS: Nutritional status directly affects immune competence; therefore, dietary supplements can be beneficial. N-acetylcysteine (NAC), a sulfur-containing amino acid, inhibits HIV replication by raising serum glutathione levels through inhibition of TNF-a.

The role of oxidative stress in disease progression in individuals infected by the human immunodeficiency virus
Baruchel S, Wainberg MA. [J Leukoc Biol 1992 Jul;52(1):111-4] This review describes the potential role of oxidative stress as a cofactor of disease progression from asymptomatic human immunodeficiency virus (HIV) infection to the acquired immunodeficiency syndrome (AIDS). An indirect argument in favor of the role of oxidative stress in HIV-associated disease progression is the consumption of glutathione (GSH), a major intracellular antioxidant, during HIV infection and progression. GSH is known to play a major role in regulation of T cell immune functions. Oxidative stress may also play an important role in the genesis of cellular DNA damage and, in this context, may be related to HIV-associated malignancies and disease progression. Finally, the role of antioxidants as components of therapeutic strategies to combat HIV disease progression is discussed.

Effects of whey protein and resistance exercise on body composition and muscle strength in women with HIV infection
Agin D, Kotler DP, Papandreou D, Liss M, Wang J, Thornton J, Gallagher D, Pierson RN Jr. [Ann N Y Acad Sci. 2000 May;904:607-9.]

Glutathione and cysteine in HIV-infected hemophiliacs
Lopez Galera RM, Juarez Gimenez JC, Montoro Ronsano JB, Segura Cardona RM, Arbos Via MA, Altisent Roca C, Tusell Puigbert JM. [Clin Chim Acta. 1996 Oct 15;254(1):63-72.]

Decreased release of glutathione into the systemic circulation of patients with HIV infection
Helbling B, von Overbeck J, Lauterburg BH. Department of Clinical Pharmacology, University of Bern, Switzerland. [Eur J Clin Invest 1996 Jan;26(1):38-44] Low glutathione (GSH) in patients with HIV infection could contribute to their immune deficiency since GSH plays an important role in the function of lymphocytes and sulphydryls decrease the expression of HIV in vitro. During infusion of GSH the concentration of cysteine in peripheral blood mononuclear cells of the HIV-infected patients increased significantly. Nevertheless, intracellular GSH did not increase. Thus, the consumption of GSH is not increased in HIV infection. Rather, the present data suggest that GSH in patients with HIV infection is low because of a decreased systemic synthesis of GSH.

Correction of glutathione deficiency in the lower respiratory tract of HIV seropositive individuals by glutathione aerosol treatment
Holroyd KJ, Buhl R, Borok Z, Roum JH, Bokser AD, Grimes GJ, Czerski D, Cantin AM, Crystal RG. [Thorax 1993 Oct;48(10):985-9] Concentrations of glutathione, a ubiquitous tripeptide with immune enhancing and antioxidant properties, are decreased in the blood and lung epithelial lining fluid of human immunodeficiency virus (HIV) seropositive individuals. Since the lung is the most common site of infection in those who progress to AIDS it is rational to consider whether it is possible to safely augment glutathione levels in the epithelial lining fluid of HIV seropositive individuals, thus potentially improving local host defence. It is feasible and safe to use aerosolised reduced glutathione to augment the deficient glutathione levels of the lower respiratory tract of HIV seropositive individuals. It is rational to evaluate further the efficacy of this tripeptide in improving host defence in HIV seropositive individuals.

Erythrocyte glutathione deficiency in symptom-free HIV infection is associated with decreased synthesis rate
Jahoor F, Jackson A, and others. [Am J Physiol 1999 Jan;276(1 Pt 1):E205-11.] "Cysteine supplementation [by one week of NAC given to HIV-infected volunteers] elicited significant increases in both the absolute rate of synthesis and the concentration of erythrocyte glutathione. These results suggest that the glutathione deficiency of HIV infection is due in part to a reduced synthesis rate secondary to a shortage of cysteine availability."

Can HIV infection be treated with antioxidants?
Muller F. Medisinsk avdeling A, Rikshospitalet, Oslo. [Tidsskr Nor Laegeforen 1995 Mar 10;115(7):835-7] Several recent reports have indicated high levels of reactive oxygen species, causing oxidative stress, in the pathogenesis of HIV infection. Oxidative stress may lead to enhanced HIV replication in infected cells and may also aggravate the immunodeficiency by reduction of cellular immunity and possibly by increased programmed cell death of lymphocytes. Moreover, reduced levels of antioxidants have been found in patients with HIV infection. This raises the question of whether antioxidant therapy might be beneficial in patients with HIV infection.

Role of cysteine and glutathione in HIV infection and other diseases associated with muscle wasting and immunological dysfunction
Droge W, Holm E. [FASEB J 1997 Nov;11(13):1077-89] Low NK cell activity in most cases is not life-threatening, but may be disastrous in HIV infection because it may compromise the initially stable balance between the immune system and virus, and trigger disease progression. This hypothesis is supported by the coincidence observed between the decrease of CD4+ T cells and a decrease in the plasma cystine level. In addition, recent studies revealed important clues about the role of cysteine and glutathione in the development of skeletal muscle wasting.... Cysteine supplementation may be a useful therapy if combined with disease-specific treatments such as antiviral therapy in HIV infection.

Role of cysteine and glutathione in signal transduction, immunopathology and cachexia
Droge W, Hack V, Breitkreutz R, Holm E, Shubinsky G, Schmid E, Galter D. [Biofactors 1998;8(1-2):97-102] Abnormally low plasma cystine levels have been found in the late asymptomatic stage of HIV infection and several other diseases associated with progressive loss of skeletal muscle mass. The phenomenon is commonly associated with a low NK cell activity, skeletal muscle wasting or muscle fatigue and increased rates of urea production. The low NK cell activity is in most cases not life-threatening but may be disasterous in HIV infection, because it may compromise the initially stable balance between immune system and virus and trigger disease progression.

Massive loss of sulfur in HIV infection
Breitkreutz R, Holm S, and others. [AIDS Research and Human Retroviruses. 2000; volume 16, number 3, pages 203-209] We now confirm the peripheral tissue as a site of massive cysteine catabolism in HIV infection and have determined the urinary loss of sulfur per time unit.... The peripheral tissue of HIV+ patients with or without highly active antiretroviral therapy (HAART) releases large amounts of sulfate and plasma sulfate, thioredoxin, and interleukin-6 levels are elevated in these patients. The abnormally high sulfate/urea ratio suggests that this process drains largely the glutathione pool."

Molecular mechanism of decreased glutathione content in human immunodeficiency virus type 1 Tat-transgenic mice
Choi J, Leu RM, and others. [J Biol Chem 2000 Feb 4;275(5):3693-8.]

Glutathione and HIV infection: reduced reduced, or increased oxidized?
Staal FJ. [Eur J Clin Invest. 1998 Mar;28(3):194-6. Review]

Micronutrient status in relationship to mortality in HIV-1 disease
Baum MK, Shor-Posner G. [Nutr Rev. 1998 Jan;56(1 Pt 2):S135-9. Review]

Antioxidant supplementation in HIV/AIDS
Segal-Isaacson AE, Rand CJ. [Nurse Pract. 1995 Jul;20(7):8, 11-4. Review.]

The role of oxidative imbalance in progression to AIDS: Effect of the thiol supplier N-acetylcysteine
Malorni W, Rivabene R, and others. [AIDS Research and Human Retroviruses. 1998; volume 14, number 17, pages 1589-1596] "Our study suggests that the redox profile of patients may be considered a predictive marker of AIDS progression and that the acute infection and the asymptomatic phase of the disease may represent a useful period in which the combined use of antiretroviral and antioxidant drugs may be beneficial."