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Chester Myers' Nutrition Series

Is a Deficiency of Cysteine, an Amino Acid, one of the Sources of Wasting in HIV Infection?

[COMMENT: additional information indicates that benefits to the immune system (Feregrino-Goyos et al, 1994), and halting of immune cell destruction by apoptosis (Montagnier, 1995) are possible by supplementing with N-acetyl cysteine (NAC)]


The 1992 International Symposium on Nutrition and HIV/AIDS highlighted the importance of nutrition in HIV and AIDS. Since then there have been numerous studies confirming the importance of vitamin/mineral supplementation, the usefulness of N-acetyl cysteine (NAC), etc. At the 1994 Third International Symposium on Nutrition and HIV/AIDS there were statements that many cases of HIV-related dementia are unnecessary if proper nutrition is provided. "Feed them" or "all is lost" were words from Dr. Donald Kotler, New York.

"Wasting" is a well-known phenomenon that often occurs with AIDS (Grunfeld, 1992; Nahlen et al, 1993). While secondary infection often seems requisite for the onset of wasting, the metabolic disturbances that cause wasting are elusive (Kotler, 1992). Particularly perplexing is that, following successful treatment of a secondary infection, lean body mass lost during the infection is often not replaced by protein (Hellerstein, 1992). Instead, regained weight frequently is fat, and this tendency is largely independent of the relative proportions of protein and fat in the diet. There is observed, however, to be a subset of people living with HIV who regain lost protein as protein (Hellerstein, 1992). Of particular importance is that the immune system requires protein in order to fight; that is, a fighting immune system cannibalizes body protein (Hunt and Groff, 1990). Fat does not provide the immune system with the same necessary energy. In such cases, stores of fat may also be quite useless because of 'futile cycling' of fatty acids (Grunfeld, 1992; Hellerstein, 1992) where calories are burned up without utilizing stored fat, using instead calories from protein stores.

While various sources of the ability to replace lost protein with protein have been investigated, one possible nutritional source seems not to have been examined. This has to do with problems in maintaining an adequate supply of cysteine. Cysteine and methionine, the two sulfur-containing amino acids, are normally considered interchangeable so that one or the other is defined as essential. Both, however, are susceptible to oxidation, and both are reduced from normal levels in patients with ARC or AIDS (Singer et al, 1992). Cysteine oxidizes reversibly to cystine, then irreversibly to cysteic acid. Once in the latter form, cysteine is no longer available for incorporation into the body's proteins and polypeptides which require it. Similarly, methionine is oxidized reversibly to methionine sulfoxide, then irreversibly to methionine sulfone. Again, once in the sulfone form, methionine is no longer available for incorporation into the body's components which require it. While it seems there is no doubt that oxidant stress is likely with HIV (abstr. TuA 66 & WB 2166 & 2421, 1991 Florence AIDS Conference; abstr. PuA 6129, PuB 7502, 1992 Amsterdam AIDS Conference; numerous publications since 1992), even in the absence of oxidation, unusual demands may make the sulfur-containing amino acids deficient. {It must not be forgotten that T cells are more susceptible to oxidation than B cells (Bendich, 1990); this is possibly a related issue particularly with respect to observations of apoptosis in lymphocytes (Olivier et al, 1992).}

Problems with maintaining the amino acid cysteine in a useable form appear to be the source of low glutathione stores during HIV infection (abstr. SA 311 & TrkB 2058, 1990 San Francisco AIDS Conference; abstr. PoA 2400, PoB 3481 & PuB 7143, 1992 Amsterdam AIDS Conference; Buhl et al, 1989; de Quay et al, 1992). An apparent "latency period of HIV infection" has even been suggested to correlate with depletion of glutathione (Baker, 1990; Kalebic et al, 1991). As early as 1990, supplementation with a modified form of cysteine, N-acetyl cysteine (NAC), was suggested as therapy (abstr. ThB 515, 1990 San Francisco AIDS Conference). NAC was later shown to maintain normal glutathione levels and to slow cell death in lymphocytes from HIV-infected individuals (abstr. PoA 2376 & 2400, 1992 Amsterdam AIDS Conference).

Low cysteine/methionine is likely to cause other problems that would result in an increasing tendency for wasting. Following are some issues that need to be addressed.
  • Glutathione is one of the body's antioxidants. Low levels result in reduced ability to fight new secondary infections, thus making subsequent weight loss likely to be more severe than in the presence of adequate glutathione levels. Moreover, glutathione transports selected amino acids into certain important cells such as in the kidneys, erythrocytes, and, perhaps, neurons (Hunt and Groff, 1990). This transport mechanism is known as the gamma-glutamyl cycle, and its importance relative to other mechanisms for amino acid transport remains uncertain. In this cycle, glutathione is broken down and reassembled in a repetitive manner. In the absence of adequate antioxidant protection it is likely that this cycling becomes a source of glutathione depletion and a strain on cysteine stores, hence also a weakening of the body's ability to maintain protein stores.
  • A protein, metallothionein, which regulates zinc and copper levels, is made of up to 30% cysteine (Cousins, 1989). Loss in the ability to regulate zinc and copper could have serious consequences for both the immune and digestive systems since both require these minerals at certain levels. A large number of the body's proteins require zinc for biological function. In the case of zinc, its 'normal' range is fairly narrow, both deficiency and excess likely to be detrimental to optimum function for both immunity and digestion. However, with HIV it is readily apparent that likelihood of deficiency is far greater than likelihood of excess, and it has been pointed out that in cases of zinc malabsorption such as with Crohn's disease, aggressive levels of from 150 to 300 mg per day of zinc intake may be necessary (Chandra, 1984). Jejunal villous atrophy that has been associated with early stage HIV-disease (Batman et al, 1989; Ullrich et al, 1989) makes zinc supplementation a special issue since the brush border membrane of the jejunum is a main site of zinc absorption. In times of zinc deprivation, the body catabolizes other metalloproteins in muscle and soft tissues (Hunt and Groff, 1990).
  • While most of the body's proteins require cysteine, the enzyme trypsin has a considerable cysteine content, and this enzyme is apparently of such importance that it is given special priority by the body metabolism so that it is maintained at the expense of other proteins when cysteine is scarcely available (Liener and Kakade, 1980). Weight loss has been suggested to result in such cases. One reason why trypsin is of special importance is that it releases other enzymes required for digestion from their precursors. Many of the body's proteins have several hundred amino acids; while there may be only one or two cysteines in a particular protein, the inability to get even one amino acid is sufficient for the protein to be prevented from fulfilling its role, e.g., formation of lean body mass.
A nutritionally related problem with glutathione is that it is oxidatively depleted by excess acetaminophen. Hospitals keep a solution of NAC, e.g., Mucomyst, for such cases of toxicity. Use of acetaminophen instead of aspirin, an antioxidant, would seem inadvisable for PLWHIV/AIDS. In one study of AZT, acetaminophen, but not aspirin, was associated with increased hematologic toxicity in the form of neutropenia (Richman et al, 1987). Alcoholism is also known to increase acetaminophen's toxicity, with depletion of the glutathione pool, overwhelming of the ability to synthesize it, and binding of its metabolites to protein thiol groups all enhanced (Kaplowitz et al, 1989). Any study to investigate a possible role for cysteine in wasting should therefore also examine use of acetaminophen-containing medications such as Tylenol. Use by both those taking NAC, and a control group not taking NAC, should give valuable information.

Since a number of PLWHIV/AIDS already supplement their diets with NAC at levels indicated to maintain normal glutathione levels (Staal et al, 1992), it is quite possible that these people have also maintained an ability to restore protein lost during secondary infection. Alternatively, those who eat diets that are high in proteins containing high levels of cysteine, accompanied by a wide range of antioxidants such as from many brightly coloured vegetables or from supplementation, may be able to maintain normal glutathione levels. These people present an opportunity for an initial investigation of a possible role of cysteine in wasting. A minimum of NAC, zinc and copper intakes would be advisable as apparently independent parameters for monitoring, using as dependent parameters the ability to maintain protein stores (such as by MIDA), levels of glutathione (intracellular or otherwise), or xylose absorption (since a source of villous atrophy may be an inadequate ability to replace the proteins required for maintenance of the jejunal cells at a sufficient rate - perhaps also of the parietal cells). Other dependent parameters could be evaluations of ambulatory ability such as by Karnofsky score testing.

Many other related trends need to be investigated - do those who supplement with vitamins E and/or C have less tendency to have altered arachidonic acid levels? What about zinc? -it may stabilize arachidonic acid against oxidative destruction (Chandra, 1990).

Author, Chester Myers, holds both honours B.Sc. and M.Sc. (1969) degrees in physical chemistry from Dalhousie University, and a ph.d. (1975) from the University of Toronto (biophysical chemistry) where he investigated the mechanism of action of a digestive enzyme. Besides publishing in the scientific literature and having authoured several patents, he has written extensively on topics regarding health and HIV. The latter include articles in The Positive Side, Canadian AIDS News, and monographs available from the AIDS Committee of Toronto (ACT), the Community AIDS Treatment Information Exchange (CATIE), and various other organizations.

The material in this publication is for information purposes only. It does not endorse any particular treatment program nor strategy; neither is it intended as medical advice nor as a replacement for medical advice.

©This document is copyrighted by Chester Myers. All materials may be reprinted and/or distributed without prior permission. However, reprints may not be edited.
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Batman, P. A., Miller, A. R. O., Forster, S. M., Harris, J. R. W., Pinching, A. J., Griffin, G. E., "Jejunal Enteropathy Associated with Human Immunodeficiency Virus Infection: Quantitative Histology", J. Clin. Pathol. 42(1989)275-281.
Bendich, A., "Antioxidant Nutrients and Immune Functions - Introduction", in Antioxidant Nutrients and Immune Functions, ed. A. Bendich, M. Phillips, R. P. Tengerdy, Plenum Press, 1990.
Buhl, R., Jaffe, H. A., Holroyd, K. J., Wells, F. B., Mastrangeli, A., Saltini, C., Cantin, A. M., Crystal, R. G., "Systematic Glutathione Deficiency in Symptom-free HIV-seropositive Individuals", Lancet 2(1989)1294-1298.
Chandra, R. K., "Excessive Intake of Zinc Impairs Immune Responses", JAMA 252(1984)1443-1446.
Chandra, R. K., "Micronutrients and Immune Functions - An Overview", in Micronutrients and Immune Functions: Cytokines and Metabolism, Ann. N. Y. Acad. Sci. 587(1990)9-16.
Cousins, R. J., "Molecular Biology and Micronutrient-Disease Relationships - Zinc as a Proto-type", in Nutrition and the Origins of Disease, ed. C. H. Halsted, R. B. Rucker, Academic Press, 1989.
de Quay, B., Malinverni, R., Lauterburg, B. H., "Glutathione Depletion in HIV-Infected Patients: Role of Cysteine Deficiency and Effect of Oral N-acetylcysteine", AIDS 6(1992)815-819.
Feregrino-Goyos M, Eid LG, Gallegos PH, Alvarada DR, Mino LD, "AZT Monotherapy Compared to AZT+DDC Combined Antiviric Therapy and AZT+DDC+NAC", abstr. PB0260, Yokohama 1994 AIDS Conference.
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Grunfeld, C., "Metabolic Disturbances, Anorexia, and Wasting in HIV/AIDS", Proc. of the 1992 International Symposium on Nutrition and HIV/AIDS including the Nutrition Algorithm and Nutrition Initiative of the Physicians Association for AIDS Care, Nutrition & HIV/AIDS, 1(1992)9-15.
Hellerstein, M. K., "Pathophysiology of Lean Body Wasting and Nutrient Unresponsiveness in HIV/AIDS: Therapeutic Implications", Proc. of the 1992 International Symposium on Nutrition and HIV/AIDS including the Nutrition Algorithm and Nutrition Initiative of the Physicians Association for AIDS Care, Nutrition & HIV/AIDS, 1(1992)17-25.
Kalebic, T., Kinter, A., Poli, G., Anderson, M. E., Meister, A., Fauci, A. S., "Suppression of Human Immunodeficiency Virus Expression in Chronically Infected Monocytic Cells by Glutathione, Glutathione Ester, and N-acetylcysteine", Proc. Natl. Acad. Sci. USA 88(1991)986-990.
Kaplowitz, N., Fernandez-Checa, J., Ookhtens, M., "Glutathione, Alcohol, and Hepatotoxicity", in Nutrition and the Origins of Disease, ed. C. H. Halsted, R. B. Rucker, Academic Press, 1989.
Kotler, D. P., "Causes and Consequences of Malnutrition in HIV/AIDS", Proc. of the 1992 International Symposium on Nutrition and HIV/AIDS including the Nutrition Algorithm and Nutrition Initiative of the Physicians Association for AIDS Care, Nutrition & HIV/AIDS, 1(1992)5-8.
Liener, I. E., Kakade, M. L., "Protease Inhibitors", in Toxic Constituents of Plant Foodstuffs, ed. I. E. Liener, 1980.
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Olivier, R., Dragic, T., Lopez, O., Herzenberg, L., Montagnier, L., "An Anti-oxydant (sic) Prevents Apoptosis and eary Cell Death in Lymphocytes from HIV Infected Individuals", abstract PoA 2376, 1992 Amsterdam AIDS Conference.
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Stahl, F. J. T., Roederer, M., Anderson, M. T., Herzenberg, L. A., Herzenberg, L. A., "Intracellular Glutathione Deficiency in AIDS: Implications for Therapy", abstract PoA 2400, 1992 Amsterdam AIDS Conference.
Ullrich, R., Zeitz, M., Heise, W., L'age, M., Hö_ken, G., Riecken, E. O., "Small Intestinal Structure and Function in Patients Infected with Human Immunodeficiency Virus (HIV): Evidence for HIV-Induced Enteropathy", Ann. Intern. Med. 111(1989)15-21.
Important Reference Sources
Advanced Nutrition and Human Metabolism, S. M. Hunt, J. L. Groff, West Publishing Co., 1990.
Annals of the New York Academy of Sciences, vol. 585 (about vitamin B6), 1990.
Antioxidant Nutrients and Immune Functions, ed. A. Bendich, M. Phillips, R. P. Tengerdy, Plenum Press, 1990.
Basic and Clinical Immunology, D. P. Stites, A. I. Terr, Appleton & Lange, 1991.
Gastrointestinal and Nutritional Manifestations of the Acquired Immunodeficiency Syndrome, ed. D. P. Kotler, Raven Press, 1991.
J. Nutrition 122(1992) - Symposium: History of Nutritional Immunology.
Micronutrients and Immune Functions: Cytokines and Metabolism, ed. G. T. Keusch, A. Cerami, F. Takaku, Ann. N. Y. Acad. Sci. 587(1990).
Nutrition and HIV Infection: A Review and Evaluation of the Extant Knowledge of the Relationship between Nutrition and HIV Infection, FASEB Life Sciences Research Office, FDA Contract No. 223-88-2124, 1990.
Nutritional Aspects of the Acquired Immunodeficiency Syndrome, P. Singer, D. P. Katz, L. Dillon, O. Kirvelä, T. Lazarus, J. Askanazi, Amer. J. Gastroent. 87(1992)265-273.
Nutrition and the Origins of Disease, ed. C. H. Halsted, R. B. Rucker, Academic Press, 1989.
Nutrition & HIV, Proceedings of the 1992 International Symposium on Nutrition and HIV/AIDS including the Nutrition Algorithm and Nutrition Initiative of the Physicians Association for AIDS Care.

August 1996
Last modified on: 09/15/2004

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