Nutrients and HIV: N-Acetylcysteine, Alpha-Lipoic Acid, L-Glutamine, and L-Carnitine

Townsend Letter for Doctors and Patients,  April, 2002  by Lyn Patrick

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Nutrients and HIV is a 3-part series written by Lyn Patrick, ND and published in the Alternative Medicine Review. Parts I and II are available for reading on the Alternative Medicine Review website: www.thorne.com/altmedrev or just use www.thorne.com. Part One: Beta Carotene and Selenium is published in Alternative Medicine Review, Vol.4, Number 5, Dec., 1999. Part Two: Vitamin A and E, Zinc, B Vitamins and Magnesium is published in Alternative Medicine Review, Vol. 5, Number One, February, 2000. Copyright 2002 Thorne Research Inc. All Rights Reserved. No reprints without written permission.

Abstract

The role of antioxidants in preventing apoptosis and viral activation in HIV is well documented. N-acetylcysteine, glutathione, and alpha-lipoic acid have been shown to interrupt the process of viral activation and CD4 cell death. L-glutamine has been shown to improve glutathione levels and significantly increase lean body mass in HIV infection. The literature on the use of L-carnitine and acetyl-L-carnitine in treating mitochondrial toxicity, both in muscle and nerve pathologies is relevant in nutritional treatment of HIV, given the mitochondrial toxicity of nucleoside analog reverse transcriptase inhibitor therapy. The current use of highly-active antiviral therapies, their toxicity, and significant failure rates have created the need for a more conservative reassessment of HIV treatment. The adjunctive use of nutrient therapy in the treatment of HIV is reviewed here.

(Altern Med Rev 2000;5(4):290-305)

The Importance of Redox Homeostasis in HIV

HIV infection and the progression to AIDS involves a long period of latent infection characterized by low levels of viral replication that slowly increase to the point of immunosuppression. (1) This progression is accelerated if the latent (non-reproducing) provirus in the nuclei of the lymphocyte is activated. (2) Oxidative stress induces both viral activation of HIV and DNA damage, leading to immunosuppression. (3-5) It is now generally accepted that a central pathologic feature of HIV disease involves oxidative stress, leading to programmed cell death (apoptosis) and depletion of CD4 cells. (6,7) It has been hypothesized by Montagnier and others (8,9) that the majority of T-helper (CD4+) cell loss (the cell most susceptible to fatal injury by HIV) actually occurs by apoptosis and not by direct HIV infection. This phenomenon has been seen in in vitro culture and in peripheral blood lymphocytes from HIV-infected patients. (10)

Evidence of increased oxidation reactions, (11) depletion of the glutathione based antioxidant defense system, (12) and increased levels of oxygen radicals have been demonstrated in the blood and tissues of HIV-infected individuals. (6) Elevated levels of hydroperoxides, (13) malondialdehyde, (14) and deficiencies of the critical antioxidant enzymes manganese superoxide dismutase, glutathione peroxidase, thioredoxin, and catalase have been demonstrated in plasma, lung lining, erythrocytes, and lymphocytes in HIVinfected individuals. (4,7,13) Nutrient malabsorption, glutathione and selenium depletion, and reduction of total thiol (cysteine) levels have all been observed to be associated with the pathology of free radical overload that leads to the cellular apoptosis of T lymphocytes. (15)

Glutathione: Antioxidant and Antiviral

Glutathione, the most abundant cellular thiol, provides the major antioxidant defense mechanism in all mammalian cells by neutralizing toxic peroxides. (16) It also helps to maintain levels of ascorbate and tocopherol by acting as a reducing agent. (17) Glutathione is necessary for maintaining immune mediated T-cell activation and phagocytosis, in addition to cellular and antibody mediated cytotoxicity, (18) and a normal balance between the T-helper cell 1 (IL-2, IL-12, gamma-interferon) and the T-helper cell 2 (IL-6, IL-4, tumor necrosis factor-alpha, IL-10, IL-1) cytokine response profile. (19) Glutathione conjugation is also the primary mechanism of eliminating electrophilic xenobiotics (some of which are carcinogens) in the liver. (20)

Glutathione deficiency has been theorized to be the cause of the increased sensitivity HIV-infected individuals have to high doses of acetaminophen and sulphamethoxazole, a medication used in the prevention of Pneumocystis pneumonia. The metabolic fate of these medications, the hepatic glutathione-S-transferase/mercapturic acid pathway, is less efficient in individuals with glutathione deficiency. (21-24) Plasma glutathione levels in HIV-infected individuals, even in the asymptomatic state, have been found to be depressed as early as three weeks post-infection. (10) Glutathione levels in lung epithelial fluid have been found to be depressed as much as 60% when compared to HIV-negative controls. (25) Intracellular glutathione levels in both infected CD4 and CD8 lymphocyte subsets are also significantly depressed; levels from 62-69% of normal have been found in the CD4 and CD8 lymphocytes of HIV and AIDS patients. (12) These figures become relevant in light of studies that show glutathione reduction of 10-40% i s capable of completely inhibiting T-cell activation in vitro. (26) While not all studies have found depressed glutathione levels in plasma or lymphocytes of infected individuals, (27,28) levels of reduced glutathione do appear to be disturbed in HIV. (29) Research assessing ratios of reduced-to-oxidized glutathione in HIV positive patients found significantly increased levels of oxidized glutathione and subsequently lower levels of reduced glutathione when compared to HIV negative controls. (30) These disturbances were greater in patients with more advanced disease, the ratios being higher than have been found in human lymphocytes in any other disease state. (30) Low serum thiol levels (precursors to glutathione) have been shown in HIV-infected, injecting drug users (IDU) to be associated with an increased risk of mortality: IDU with low serum thiol levels are 5.65 times more likely to experience an accelerated time-to-death. (5)