Some immune stimulating treatments and the scientific bases for them

John Kirkham and James Whitehead

Here are some of the treatments that our members are seeking or are using already. Many would prefer to use these agents working with co-operative doctors and health care professionals.


Anti oxidant therapies : including: S-Acetyl-L Glutathione, NAC , Selenium, Vit B complex, Vit C, Vit E, Vit A, Acetyl-L-Carnitine, Alpha Lipoic Acid, Padma 28, Pycnogenol.

A whole extra dimension of effective, non-toxic and inexpensive treatment is shut off because there is no NHS provision. This is an appeal to support the right of access of HIV positives and people diagnosed as AIDS to non-toxic, immune enhancing treatments, reducing agents, anti- wasting agents. It is scandalous that after spending hundreds of billions of dollars on AIDS research, the possibility of protecting and boosting the immune system rather than combating HIV receives very little attention.

It has been found that AIDS is characterised by a persistent oxidative imbalance. An increasing deficiency of the non-toxic anti-oxidant glutathione plays a crucial role in the transition from pre-AIDS to full blown disease (1,2) To quote from Montagnier (the discoverer of HIV) et al (3):

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"A large body of data on in vitro human immunodeficiency virus (HIV) infection and biochemical clinical studies suggests that oxidative stress plays a role in AIDS pathogenesis*. Recent reports have implicated intracellular excess of reactive oxygen species (ROS) in the induction of HIV expression (4-7) and in the initiation of apoptotic cell death ** (8). Studies showing a decrease in glutathione in peripheral blood mononuclear cells from symptom-free persons offer further evidence of a metabolic alteration leading to the decreased ability to counteract oxidative stress (9). These findings, together with other alterations of biochemical indicators of systemic oxidative damage that have been observed (10-12) suggest that antioxidants can be useful in inhibiting viral replication and cell death in patients with HIV infection and AIDS"

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"It has been suggested that oxidative stress is a common mediator of apoptosis (8). This hypothesis stems from experimental evidence that oxidative stimuli induce apoptosis (13-15) while antioxidants inhibit it."

"In AIDS pathogenesis oxidative stress is proposed as a metabolic alteration that favours disease progression by inducing both viral replication and apoptotic death"

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"Indeed, evidence that oxidative stress induces, while antioxidants inhibit, HIV replication and apoptosis suggests the use of these molecules as an antiretroviral therapy to reduce cell death in AIDS patients"

In 1983 Luc Montagnier and in 1984 Robert Gallo stimulated cell cultures from tissues of AIDS patients with numerous oxidising (16) and mitogenic chemical agents and observed a number of phenomena which, long before the AIDS era, were known to be non-specific. By 1986 Montagnier and Gallo acknowledged that the "HIV" phenomena cannot be detected unless the cells are stimulated (17, 18). Subsequently researchers including Anthony Fauci, showed that when stimulated cell cultures are treated with reducing agents this greatly suppresses the appearance of such phenomena (4). >From the beginning of the AIDS era there has been evidence that individuals belonging to the AIDS risk groups are exposed to oxidising agents. In a 1998 study, researchers from Canada reported that supplementation of vitamin E and C reduces oxidative stress in "HIV" positives and produces a trend towards a reduction in "viral load"(19). I quote:

"This study is the first randomised controlled trial to demonstrate that, in an HIV-positive population, daily supplementation of 800 IU vitamin E and 1000 mg vitamin C significantly decreases oxidative stress and produces a trend towards a reduction in HIV viral load suggesting that there may be some clinical benefit worthy of larger clinical trials. Since combination antiretroviral therapies containing protease inhibitors are limited for economic reasons to only about 10% of HIV infected individuals in the world, consideration of the potential for this antioxidant therapy remains important for the developing world. It could have great benefit, perhaps similar to the effect of vitamin A supplementation on childhood mortality in developing countries."

"Montagnier and his associate David Klatzmann were the first to draw attention to the fact that LAV infection of T4 cells in vitro does not lead to HIV expression unless the cells are stimulated. "Infection of resting T4 cells does not lead to viral replication or to expression of viral antigens on the cell surface, while stimulation by lectins or antigens of the same cells results in production of viral particles, antigenic expression and the cytopathic effect" (Klatzmann and Montagnier, 1986). Gallo also expressed the view that without "activation" the T4 cells do not express virus (Zagury et al., 1986). But, apparently, they did not realise that oxidative phenomena are implicated in human T-cell stimulation (Sekkat et al., 1988)." (69)

"Glutathione (GSH), a cysteine containing tripeptide is essential for the viability and function of virtually all cells. 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 Š 3 years after baseline data collection. This finding, supported by evidence that oral administration of the GSH prodrug N-acetyl cysteine and suggesting that N-acetylcysteine administration can improve their survival, establishes GSH deficiency as a key determinant of survival in HIV disease further it argues strongly that the unnecessary or excessive use of acetaminophen, alcohol or other drugs known to deplete GSH should be avoided in HIV infected individuals. (2)"

"Reduced plasma cysteine was significantly (p < 0.0001) lower in HIV-positive patients (13.0 +/- 3.0 ?M) when compared with control subjects (16.9 +/- 3.0 ?M). Although there was no difference in oxidized, protein-bound, and total cysteine, the thiol/disulfide ratios were lower in HIV-positive patients."(40)

"Mitochondrial oxidative damage is implicated in brain aging and in age-related neurodegenerative diseases. Since N-acetylcysteine (NAC) has recently been shown to prevent apoptotic death in nerve cells and protect mitochondria proteins from free radical damage in aged mice, a study investigated whether dietary administration of this NAC slows age-related memory loss. Mice received pellets containing 0.3% (w/w) of NAC. After 23 weeks of this diet, the NAC had partially restored the memory deficit associated with aging in mice. Moreover, the Lipid peroxide and protein carbonyl contents of the synaptic mitochondria were significantly decreased in the NAC-supplemented animals in comparison with their age-matched controls. The antioxidant properties and probable action on mitochondrial bioenergetic ability in the synaptic terminals may explain, at least partially, the beneficial action of NAC administration."(38).

"After developing a test to measure mitochondrial activity, Nath and colleagues then compared spinal fluid of 30 patients with HIV dementia --16 patients lacking symptoms and another 20 patients with other neurological problems, including multiple sclerosis and chronic headaches. They found that in HIV patients, mitochondrial activity was incrementally depressed as HIV levels increased in the CSF of patients and dementia progressed." "CSF from patients with HIV infection causes mitochondrial dysfunction with increasing severity of dementia," Nath said. "Next we tested several antioxidant preparations known to protect the mitochondria in the cell cultures to see what effect if any they might have. "We found six out of seven of these antioxidants reduced the toxicity level of the CSF and protected the mitochondria in these cell cultures. We were quite surprised." (41)

"We sought evidence that azathioprine causes cell death through reduced glutathione (GSH) depletion and mitochondrial injury." (73) The mechanism of azathioprine toxicity to hepatocytes involves depletion of GSH leading to mitochondrial injury with profound depletion of ATP and cell death by necrosis. Cell death was prevented by potent antioxidants, glycine and blocking the mitochondrial permeability transition pore." . (73). "To investigate the role of decreased GSH content in the toxicity of thiram, GSH levels were modulated prior to exposure. Pretreatment of fibroblasts with N-acetyl--cysteine (NAC), a GSH biosynthesis precursor, prevented both lipid peroxidation and cell death induced by thiram exposure. In contrast, thiram cytotoxicity was exacerbated by the previous depletion of cellular GSH by -buthionine-(S,R)-sulfoximine (BSO). Taken together, these results strongly suggest that thiram induces GSH depletion, leading to oxidative stress and finally cell death." (74)

"The mechanism for nucleoside analogue -related PN is thought to be impaired neuronal mitochondrial DNA synthesis and repair which disrupts energy metabolism causing die-back of long peripheral axons. L-acetyl carnitine is an amino acid that enhances retrograde neurotrophic support of sensory neurons, and which suffers a decrease in serum levels in HIV neuropathy.

This open observational cohort study by Mike Youle performed lower leg skin biopsies on four patients with established PN (Grade 2-4) before and after 6 months oral LAC treatment (1500mg BID). Frozen sections were immunostained using fibre-type specific primary antibodies (PGP, GCRP, VIP) and FITC-labelled secondary sera, and were examined by fluorescence microscopy and optimized by digital photography. All sections were stained and analyzed at the same time. The system used for computerized image analysis for each of three skin areas (epidermis, dermis and ecrine sweat glands) has already been validated for use in diabetes-related neuropathy.

Results showed an increase in area of immunostaining of 40% (p=0.22) for all fibre types and 493% (p=0.002) for small sensory fibres. The study noted a trend towards greater percentage increases with increased duration of neuropathy. In sweat glands the mean increase was 293% (p<0.001) for all nerve fibres and 273% (p<0.001) for sympathetic efferents.

All patients reported an improvement in symptoms and three of these four patients had continued nucleoside treatment throughout the study. Clinical grade of dysaesthetic pain improved from grade 3-4 at baseline to grade 1-2 following treatment with LAC. [11] ."(39)

"A study of antioxidant rescue in mice treated with NRTI's was presented by Jay Lenhard from Glaxo Wellcome, Research Triangle Park, NC, USA [5]. In this mice were treated with placebo or NRTI's for 2 weeks with or without concomitant anti-oxidants, ascorbate and alpha-tocopherol. Whilst the presence of the NRTI's clearly induced metabolic changes and damage to the oxidative phopshorylation pathway of energy production within the mitochondria, the presence of the antioxidants produced a marked 70% reduction in this damage. (39)".

"Peripheral neuropathy (numbness/tingling/burning in the feet and sometimes, hands) occurs in up to one-third of persons with HIV infection. Any one of three NRTI (nucleoside reverse transcriptase inhibitor) drugs also can cause the condition. Those are the so-called "d drugs," including ddC (Hivid, zalcitabine), ddI (Videx, didanosine) and d4T (Zerit, stavudine). Peripheral neuropathy also is caused by diabetes, the antibiotics dapsone and isoniazid (INH), vitamin B12 deficiency, chronic alcoholism, leprosy and those who have had cancer chemotherapy with vincristine. In HIV, peripheral neuropathy is associated with toxicity to "mitochondria," (energy producing component of cells) which may be caused to varying degrees by drugs within the NRTI class." "Michael Youle, MD, from the Royal Free Center for HIV Medicine in London, UK, presented the results of a small observational study with the conclusion that oral L-acetyl carnitine improved symptoms of peripheral neuropathy. Also, those improvements correlated with increased nerve tissue staining from biopsies in four patients." (39)

"An initial lactate level of 9 mmol/L, which gave good positive and negative predictive values, was determined as a threshold between survivors and nonsurvivors for the patients receiving nucleoside-analog treatment. Six patients with initial lactate levels >10 mmol/L were prospectively treated with l-carnitine; three survived beyond the end of the study."(51). "The blood lactate levels in human immunodeficiency virus patients receiving nucleoside-analog therapy can predict mortality in these patients. The preliminary data from this pilot study suggest that l-carnitine may be helpful for patients who have nucleoside-analog-related lactic acidosis with blood lactate levels >10 mmol/L. Further studies will be necessary to affirm the therapeutic efficacy of l-carnitine in this setting." (51).

"The second factor that is involved is that there must be hyper-activation of the immune system. What is striking in HIV infection is that abnormal activation (T cell receptor stimulation) of infected cells is continuous and lasts throughout the entire course of the disease, including pre-clinical and clinical stages. Apoptosis (programmed cell death) occurs rapidly after lymphocyte cell activation."(27). "(Although the infection appears to be dormant, the virus is replicating actively in lymph nodes and lymphatic tissue and apoptosis is occurring.)" (27) Oxidative stress is a key factor. There is a higher free radical production in stage II of HIV infection that could be caused by several factors including the overproduction of oxygen radicals by polymorphonuclears. The key may be to reduce oxidative stress at the earliest stage of HIV infection." (27)

Montagnier: "I strongly believe that one important factor is the activation of the T-helper cells. Consecutive T-cell receptor stimulation induces T-cell deletion by apoptosis. [4] Recognizing the importance of apoptosis in AIDS progression may have dramatic implications for developing new treatments for AIDS. Apoptosis may induce oxidative stress. We know also that oxidative stress can mediate apoptosis. This is a circular cascade."(27)

"The Fas/Fas ligand system is involved in uncontrolled apoptosis, which ultimately leads to the loss of T lymphocytes in human immunodeficiency virus (HIV)-infected individuals" (57). "Our recent reports have shown that L-carnitine inhibits Fas-induced apoptosis and ceramide production both in vitro and in vivo. The aim of this study was to study, in a preliminary fashion, the impact of long-term L-carnitine administration on CD4 and CD8 absolute counts, rate, and apoptosis in HIV-1-infected subjects".(57)

"Eleven, asymptomatic, HIV-1-infected subjects, who refused any antiretroviral treatment despite experiencing a progressive decline of CD4 counts, were treated with daily infusions of L-carnitine (6 g) for 4 months." (57) "L-carnitine therapy resulted in an increase of absolute CD4 counts, which was statistically significant on day 90 and 150 (P = .010 and P = .019, respectively). A positive, not significant trend was also observed even in the change in absolute counts of CD8 lymphocytes. L-carnitine therapy also led to a drop in the frequency of apoptotic CD4 and CD8 lymphocytes. This reduction occurred gradually, but changes in actual values between each time point and baseline were strongly significant (P = .001 at the end of the study compared with the baseline). A strong reduction (P = .001) in cell-associated ceramide levels was found at the end of the study. In general, HIV-1 viremia increased slightly. No toxicity related to L-carnitine therapy was observed and dose reductions were not necessary. In HIV-1-infected subjects, long-term infusions of L-carnitine produced substantial increases in the rate and absolute counts of CD4 and, to a lesser degree, of CD8 lymphocytes. This was paralleled by a reduced frequency of apoptotic cells of both subgroups and a decline in the levels of ceramide. No clinically relevant change of HIV-1 viremia was observed."(57).

"Lymphocytes from subjects infected with the human immunodeficiency virus type 1 (HIV-1) undergo an inappropriate programmed cell death (apoptosis), a major mechanism for the decline of CD4 and CD8 cells that is crucial to the progression towards the overt acquired immunodeficiency syndrome (AIDS).1-8 Indeed, lymphocyte apoptosis correlates with disease progression and lower CD4 counts: a high degree of apoptosis has been detected in patients with AIDS in comparison with long-term nonprogressors.1-8."(57). "Patients with AIDS have significantly higher lymphocyte-associated ceramide levels than healthy individuals and HIV-1-infected long-term nonprogressors have less elevated lymphocyte-associated ceramide levels than subjects with evolving disease.8,20,21 Remarkably, this is paralleled by a lower frequency of apoptotic CD4 and CD8 cells in long-term nonprogressors than in patients with AIDS.8,21".(57)

"All of the subjects reported, with no exception, a sense of improved well-being by the second week of L-carnitine treatment." (57).

"The analyzed individuals represent a unique population of infected subjects, all of whom were living in the Community of San Patrignano, being exposed to the same environmental influences and with comparable nutritional regimens. Remarkably, in the majority of individuals, there was a past history of HBV or HCV infection and no opportunistic infection was detected during the trial period."

"Taken together, our data suggest that long-term L-carnitine administration may have a substantial impact on the chief immunologic abnormality associated with HIV-1 infection, the loss of CD4 T cells, through downmodulating the generation of ceramide and reducing the rate of apoptotic lymphocyte death, without affecting the HIV-1 viremia levels, thus suggesting that a dissociation exists between changes in viremia and CD4 depletion." (57)

"Additional mechanisms contributing to the antiapoptotic effects of L-carnitine, beside the inhibition of ceramide generation, cannot be ruled out, as shown by recent studies reporting its ability to prevent the disruption of mitochondrial transmembrane potential,31,32 an early and irreversible step in the effector phase of apoptotic cell death.33 Moreover, an abnormal redox cellular state is associated with HIV infection and could be at least partially involved in the T-cell depletion in AIDS.34,35 Indeed, oxidative stress has been implicated in apoptosis, and it may provide effector mechanisms for the final common pathway of programmed cell death. L-carnitine, when administered in vivo, is very effective in inhibiting oxygen radical production.36 Thus, the antiapoptotic effect of L-carnitine could also be due to its antidepolarizing action at the mitochondrial level and antioxidant activity." (57)

"The potential of L-carnitine to protect the host against the toxicity of nucleoside analogs adds further weight to this idea. 37-40." (57)

The addition of L-carnitine is safe and allows apoptosis and oxidant stress to be greatly reduced in lymphocytes from subjects treated with AZT and DDI." (58)

Montagnier: "Being able to reduce apoptosis to a normal rate in lymphocytes of HIV-infected individuals would put HIV infection in a class with mononucleosis and other chronic infections where cell death does occur, but the immune system goes back to normal after a period of time. In the middle and later stages of HIV infection, apoptosis is a chronic and permanent problem. Antioxidants including NAC might slow the rate of apoptosis. Apoptosis is not limited to HIV infection, but proceeds at a higher rate in HIV-infected cells." (27)

"Other cofactors may be some ordinary proteins or some external factors which are present before infection or even carried along with the HIV, and oxidative stress. If we act on the causative agents that lead to increased apoptosis -- free radicals, microbial factors, viruses -- or interact with the many steps of the apoptosis process, we can reduce cell death to a normal rate."(27)

"We should treat oxidative stress at the earliest possibility. This requires measuring the oxidative stress markers in the blood and tailoring the treatment to the individual based on the results of these tests." (27)

"I am convinced that oxidative stress is indeed involved in the progression of going from HIV infection to the AIDS stage. I believe, therefore, that antioxidants are necessary in the treatment , but antioxidants are not sufficient by themselves."(27).

"Montagnier: This concept was put forth by Gene Shearer and Mago Clerici at NIH. There is still some debate about it. It seems that it is not a clear cut switch, but that there are some changes. What is observed in patients progressing to AIDS, is an increase of cytokines which are involved in T-helper 2 immunity which promotes B-lymphocytes, but inhibit the cellular immunity important in controlling HIV infection."(27).

"Glutathione levels in antigen-presenting cells determine whether Th1 or Th2 response patterns predominate"(43). "Increasing glutathione levels helps reduce a Th2 dominance." (43). "All of these agents display a wide variety of pharmacologic effects; however, they intersect in their ability to deplete GSH and to alter immune function. Furthermore, we have shown that treatment with NAC, a GSH prodrug, reverses the in vivo immunomodulating effects of low-dose CY; and others (34) have shown that supplementing cultures with NAC decreases IL-4 production.

Together, these findings persuasively argue for a key role for APC GSH in determining whether antigenic simulation inducted a Th1 or Th2 response pattern." (43) . "Current thinking attributes the balance between T helper 1 (Th1) and Th2 cytokine response patterns in immune responses to the nature of the antigen, the genetic composition of the host, and the cytokines involved in the early interaction between T cells and antigen-presenting cells. Here we introduce glutathione, a tripeptide that regulates intracellular redox and other aspects of cell physiology, as a key regulatory element in this process. By using three different methods to deplete glutathione from T cell receptor transgenic and conventional mice and studying in vivo and/or in vitro responses to three distinct antigens, we show that glutathione levels in antigen-presenting cells determine whether Th1 or Th2 response patterns predominate. These findings present new insights into immune response alterations in HIV and other diseases. Further, they potentially offer an explanation for the well known differences in immune responses in "Th1" and "Th2" mouse strains.". "In general, the Th1 pattern is characterized by interleukin 12 (IL-12) and interferon (IFN-) production and the up-regulation of cell-mediated, e.g., delayed hypersensitivity (DTH), responses (4, 5). The Th2 response pattern is characterized by IL-4 and IL-10 production and the up-regulation of a variety of antibody responses." (43).

"A wide range of human diseases are associated with altered levels of GSH (43), including cancer (44) and AIDS (45). Indeed, we have recently shown that GSH deficiency in HIV-infected individuals correlates with decreased survival during a 2- to 3-year monitoring period (46). This diminished survival capacity could be due to any or all of the multiple metabolic and regulatory functions of GSH. Our findings here, however, suggest that alteration in immune function because of GSH depletion in APC populations may play a key role in exacerbating HIV and other infectious diseases in which Th2 predominance is an important aspect of the disease pathology"(43).

"A characteristic for the transition from asymptomatic HIV infection to AIDS-related complex and to full-blown AIDS is the continual reduction in the number of CD4-lymphocytes in the blood while the CD8-lymphocyte count remains practically constant. According to current wisdom, this is because of the increasing destruction of CD4-cells by HIV."

Last year however, Carbonari et al showed that apoptotic (apoptosis = programmed cell death) lymphocytes in AIDS patients consist for the most part of CD8 T-cells and CD19 B-cells.(1) They concluded from this that the phenomenon of in-vitro apoptosis might not be related to the depletion of CD4 T-cells in AIDS. Finkel et al recently showed that apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes.(2) In their commentary, Pantaleo and Fauci did not wish to give any conclusive answer to this.(3) (44)

"Mosmann and Coffman showed in 1986 that the CD4-lymphocytes can be divided into two cell-groups, known as Th-1 and Th-2 cells (This an abbreviation for T-helper cell).(12) The Th-1 cells secrete mainly Interleukin (IL)-2, IL-12 and Interferon (IFN)-gamma, which are chemical messengers which stimulate cellular immune reactions. The Th-2 cells secrete mainly IL-4, IL-6 and IL-10 which stimulate the humoral immune reactions." (44)

"The significant step towards clarification of the mechanisms behind production of these chemical messengers known as cytokines was made by the study group around Daynes.(13,14) This group revealed first of all that regulation of the cytokine production of activated lymphocytes takes place in the periphery. Mitogen (a substance which activates cells to divide)- or antigen-stimulated lymphocytes from lymphoid organs of the mucus membranes produce mainly IL-4. Lymphocytes from internal organs produce mainly IL-2.

Taken from recent highlights 9th retrovirus convention "Alan Perelson, a collaborator of Dr. Ho, discussed results of experiments that used deuterated ("heavy") glucose and measured its incorporation in the DNA of newly dividing, proliferating CD4+ and CD8+ T cells. His mathematical predictions assumed that the rate of new cells supplied by the sources and the rate of cell death or destruction was pretty much equal because CD4+ and CD8+ T cell counts do not change much over a short period of time. In HIV+ persons, the proliferation rates of CD4+ and CD8+ T cells were shown to be 6 fold and 8 fold higher than in HIV-negative persons. For CD4+ T cells, the source rate was 4 fold higher while death rate was 3 fold higher than in HIV-negative controls, but was unchanged for CD8+ T cells."(75). " Like Dr.Perelson, he also found high turnover of both types of cells. He took his analysis one step further by studying whether the cells were naïve (or "resting") or activated ("memory"). He found that the naive cells were slowly proliferating and that the activated cells were rapidly proliferating." (75). "An important lesson from the session appeared to be that unless experiments directly measure the phenomenon in question, experiments that measure surrogate or indirect phenomenon depend upon assumptions about the relation to the phenomenon in question which may ultimately be incorrect and lead to erroneous interpretation." (75).

The decisive factor for the type of peripheral regulation of lymphocyte cytokine production is the production of steroid hormones which are produced locally from inactive precursors. In this process the dehydroepiandrostosterone (DHEA) produced in the cortex of the adrenal glands plays an important role as an antagonist to cortisol. DHEA is the adrenocortical hormone contained in the blood in the highest concentration of all the steroid hormones.

In its sulphated form, DHEAS, it is inactive. By means of steroid sulphatase, DHEAS is desulphated in the periphery and thus transformed into DHEA, the active form. In the lymphocytes the active DHEA causes increased production of IL-2 and IFN-gamma, but not of IL-4. These findings have revealed that the varying concentration of steroid sulphatase in different tissues during the transformation of the pre-hormone DHEAS into active DHEA plays a central role in the production of Th-1 and/or Th-2 CD4-lymphocytes.

In the lymphatic tissue the macrophages are the only cells that have an appreciable quantity of DHEAS sulphatase. Moreover the high concentration of circulating DHEAS is used for the production of androgenic (male sex) and secondarily of oestrogenic (female sex) hormones. After what has been said it seems plausible to us to consider the sequestration of CD4-lymphocytes to the bone marrow as a significant component of a stress-induced Th-2 profile of CD4-lymphocytes, because in the Th-2 profile in the bone marrow CD4-cells actively stimulate the B-cells, present there in large numbers, to increase the formation of antibodies."(44)

"The mechanism(s) by which human immunodeficiency virus (HIV) causes depletion of CD4 lymphocytes remains unknown. Evidence has been reported for a mechanism involving HIV binding to (and signaling) resting CD4 lymphocytes in lymphoid tissues, resulting in up-regulation of lymph node homing receptors and enhanced homing after these cells enter the blood, and induction of apoptosis in many of these cells during the homing process, caused by secondary signaling through homing receptors. Supportive evidence for this as a major pathogenic mechanism requires demonstration that CD4 lymphocytes in HIV+ individuals do migrate to lymph nodes at enhanced rates. Studies herein show that freshly isolated CD4 lymphocytes labeled with 111Indium and intravenously reinfused back into HIV+ human donors do home to peripheral lymph nodes at rates two times faster than normal. They also home at enhanced rates to iliac and vertebral bone marrow". (61). "The results support the theory that the disappearance of CD4 lymphocytes from the blood of HIV+ patients is a result of their enhanced migration out of the blood (homing) and dying in extravascular tissues." (61).

"In the mid-'70s Fauci and his working group showed that after the administration of cortisol (a hormone produced by the adrenal glands in response to stress) the body appeared to respond with a selective reduction in the number of CD4-cells. This was found to be because most of this sub-group of white blood cells migrated from the blood circulating in the blood vessels into other areas of the body outside the vascular system.(4,5,6) After the withdrawal of cortisol, the CD4-cells return to the circulating blood and CD4/CD8 ratio returns to normal.

With regard to where the CD4-cells migrate under the influence of cortisol, it has been shown in animal experiments that they are sequestered mainly into the bone marrow.(4,7,8) Following these studies Antonacci and Calvano, from the working group of Shires, showed that a similar depletion of CD4-cells is also seen in burn patients.(9) Calvano also demonstrated that in cases of burns the body's own bioactive cortisol level rises sharply.(10) These investigators concluded from their findings that the sequestration of CD4-cells to bone marrow may be considered as a general phenomenon in any severe and persistent hypercortisolism (an excess of cortisol in the blood) in acute-phase inflammatory reactions in which the whole body responds to an inflammation or injury." (44)"Since the outset of the 1990s, it has been proven in human beings that there are two subgroups of T4 cells, as with all mammals.These are not differentiated in laboratory measurements by HIV/AIDS researchers. Yet the T4 cell count in the blood stream is determined by the relationship of these two subgroups called TH1 and TH2. Dominant TH2 cells are formed by lack of cysteine and glutathione. They have migrated from the blood stream and stimulate antibody production in the lymph organs. The number of these T4 cells in the bloodstream declines automatically. This "switch" in the T4 cell balance - as in the case of cancer cell transformation - is regulated by type-2 cytokine. If it is lasting, it causes the disposition for AIDS. As has been proved, the really endangered among the "HIV positives" have type-2 cytokine dominance." (68) More recently, researchers in the European Union have been studying the impact of ecstasy on the immune systems of mice and people and have found some troubling data.

"Researchers enrolled 17 healthy (HIV-uninfected) male subjects for a series of short, placebo-controlled studies of ecstasy. Subjects received 100mg ecstasy once or twice over a period of 24 hours. Blood samples were collected before, during and after the study.Results: a single doseThe researchers found that a single dose of ecstasy (100mg) taken by mouth caused a dramatic fall in the level of immune system cells called T cells, which are needed to help fight infections. The number of a specific group of T cells, called CD4+ cells, decreased by about 30% within hours after a single dose of ecstasy. Fortunately, within a day after taking this dose, CD4+ cell levels returned to normal.Results: two doses.Among subjects who received two doses of the drug, four hours apart, the decline in CD4+ cells was even more serious, reaching a level 40% below normal. Although a day later T-cell levels rose, they did not return to normal.Another important finding is that ecstasy clearly reduced the ability of T cells as well as other immune system cells to fight infections. Why is ecstasy not immune friendly?Perhaps these results should not be surprising as ecstasy is chemically related to another group of chemicals called amphetamines. This group of drugs does not enhance the health of the immune system. The research team also found that exposure to ecstasy causes the body to produce increased amounts of the hormone cortisol. This hormone probably caused the CD4+ cell count to temporarily fall because these cells moved from the blood to the lymph nodes and tissues. They returned to the blood once cortisol levels returned to normal. Higher than normal cortisol levels may also have been the reason that the immune cells' ability to fight infections was reduced. In people with HIV/AIDS who use ecstasy, the drug therefore has the potential to increase levels of HIV.Furthermore, ecstasy can rise to dangerous levels among patients who also use anti-HIV drugs known as protease inhibitors and non-nucleoside reverse transcriptase inhibitors." (76) "The University of California report found no harmful changes in HIV levels in the participants when they either smoked marijuana or took the oral cannabinoid dronabinol. In HIV-infected patients, marijuana has been used as an appetite stimulant and as a treatment for the nausea associated with some antiretroviral medication. But, in the past, concern has been raised that such therapy could have a harmful effect on disease status. (77) "The subjects were divided into three groups: 20 smoked marijuana, 22 received dronabinol, and 20 received an oral placebo." (77)" Researchers measured changes in HIV levels in the blood of the volunteers as well as their CD4 counts. In all three groups, patients with detectable levels of HIV had no change in the levels of virus in their blood. ( 77). "However, CD4 cell counts actually increased about 20 per cent for both the groups that received cannabis - while there was no change in the CD4 of the placebo group.". "This month a study by the Medical Research Council aims to find out if cannabis can help to relieve pain - where the patients actually receive capsules containing standardised cannabis extract". (77) "Taken together, our data suggest that long-term L-carnitine administration may have a substantial impact on the chief immunologic abnormality associated with HIV-1 infection, the loss of CD4 T cells, through downmodulating the generation of ceramide and reducing the rate of apoptotic lymphocyte death, without affecting the HIV-1 viremia levels, thus suggesting that a dissociation exists between changes in viremia and CD4 depletion." (57).

"Impaired neuroprotection resulting from oxidative stress has been implicated in neurodegeneration in a number of pathologic conditions of the brain, including both subcortical and cortical type dementias. Production of excessive oxidative stress, moreover, can lead to elevated levels of certain proinflammatory cytokines that are considered to be contributing factors to neuronal injury and are evident in HIV-related dementia as well as in other neurodegenerative conditions. Inhibitors of oxidative damage could thus be promising therapeutic agents for preventing progressive nerve cell death and slowing the advance of neurodegenerative disease. The potential of antioxidant therapy to provide neuroprotection is substantiated by studies demonstrating reduced oxidative stress with supplementation and lower risk for cognitive impairment with higher plasma antioxidant levels." (31)

"Glutathione deficiency induced in newborn rats by giving buthionine sulfoximine, a selective inhibitor of glutamylcysteine synthetase, led to markedly decreased cerebral cortex glutathione levels and striking enlargement and degeneration of the mitochondria. These effects were prevented by giving glutathione monoethyl ester, which relieved the glutathione deficiency, but such effects were not prevented by giving glutathione, indicating that glutathione is not appreciably taken up by the cerebral cortex.". (65).

"Results suggest that the neuroprotective effect on the brains in old rats was achieved by the elevation of antioxidants with L-carnitine." (65)

"Malnutrition, and selenium levels of 135 g/L (patients with these levels were 13 times more likely to develop mycobacterial disease). (32)

"Multivariate analyses controlling for antiretroviral treatment and CD4 cell count revealed that both body mass index and selenium level remained significant factors in the relative risk for developing mycobacterial disease (relative risk, 3; p = .015); these findings suggest that selenium status may have a profound impact on the pathogenesis of mycobacterial disease."(32)

"These results indicate that selenium deficiency is an independent predictor of survival for those with HIV-1 infection."(34)

"Over the course of the study, 12 children died of HIV-related causes. The final Cox multivariate analysis indicated that, of the variables evaluated, only CD4 cell count below 200 (risk ratio [RR] = 7.05; 95% confidence interval [CI], 1.87-26.5); p = .004], and low levels of plasma selenium (RR = 5.96; 95% CI, 1.32-26.81; p = .02) were significantly and independently related to mortality."(35)

"Among the children who died, those with low selenium levels (85 g/L), died at a younger age, suggesting more rapid disease progression "Conclusions: In pediatric HIV-infection, low plasma level of selenium is an independent predictor of mortality, and appears to be associated with faster disease progression."(35)

"SIV-infected monkeys show a decrease in blood selenium levels similar to that observed in AIDS with development of SAIDS. Cells infected with SIV in vitro exhibit reduced selenoprotein levels and an accumulation of small molecular weight selenium compounds relative to uninfected cells. Examination of the selenocysteine tRNA isoforms in HIV-infected KK1 cells or SIV-infected CEMx174 cells reveals an isoform distribution characteristic of selenium-deficient cells. Furthermore, transfection of Jurkat E6 cells with the Tat gene selectively altered selenoprotein synthesis, with GPX4 and Sep15 being the most inhibited and TR1 the most enhanced. Taken together, the data show that monkeys infected with SIV in vivo and cells infected with SIV in vitro will provide appropriate models for investigating the mechanism(s) responsible for reduced selenium levels that accompany the progression of AIDS in HIV disease". (45) .

"Serum selenium levels were determined cross-sectionally in 104 sequentially selected HIV-infected patients (83 outpatients and 21 patients with ongoing AIDS defining events). The patients were classified into three stages of the disease, I, II and III according to the 1993 Centers For Disease Control (CDC) classification system for HIV-infection. GSH-Px activities, plasma SH and plasma GSH concentrations were determined in a subset of 24 patients at stage I and 12 patients at stage III with an active AIDS-defining disease. RESULTS: Mean serum selenium levels were lower in CDC stage II (68.7 +/- 20.9 micrograms/l; P < 0.01; n = 34) and stage III (51.4 +/- 14.7 micrograms/l; P < 0.01; n = 37) HIV-infected patients than in healthy subjects (89.2 +/- 20.9 micrograms/l; n = 72) and stage I patients (82.3 +/- 20.5; microgram/l; n = 33). Serum selenium levels were positively correlated with CD4-count (r = 0.42; P < 0.001; n = 104) and inversely with levels of soluble tumor necrosis factor receptors type II (r = -0.58; P < 0.01; n = 35), neopterin (r = -0.5; P < 0.001; n = 80) and beta 2-microglobulin (r = -0.4; P < 0.001; n = 94). Hepatitis C virus (HCV) and HIV-coinfected patients at CDC stages I and II showed markedly lower selenium concentrations compared to HIV-infected patients without concomitant HCV-infection. Serum selenium and GSH-Px activity in hospitalized AIDS patients was significantly lower as compared to asymptomatic patients and healthy subjects, whereas plasma SH and GSH concentrations were lower in both, asymptomatic -and AIDS-patients, than in the controls. CONCLUSION: The results show that stages I-III of HIV-disease are characterized by significant impairments of antioxidative defenses provided by selenium, GSH-Px, SH-groups and GSH."(37)

"Glutathione (GSH), its derivatives and N-acetylcysteine (NAC) inhibit the induction of HIV-1 expression in a chronically HIV-1-infected promonocytic cell line (U1/HIV) and peripheral blood mononuclear cells (PBMC)."(33) "Infection was blocked or substantially reduced by GSH or NAC (5-20 mM). Significant reduction (greater than or equal to 90%) in the amount of virus released, as determined by measuring supernatant reverse transcriptase activity and secreted p24 protein, was obtained when the cells were treated for 4 h with greater than or equal to 10 mM of GSH or NAC. 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." (33)

"In 1985, Pompidou et al. (1985b) and more recently many other researchers including Anthony Fauci have shown that reducing agents suppress the expression of HIV (Scheib et al., 1987; Bitterlich et al., 1989; Kalebic et al., 1991)." (69)

"HIV-infected individuals and SIV-infected rhesus macaques have, on the average, decreased plasma cysteine and cystine concentrations and decreased intracellular glutathione levels. We show that the cysteine supply and the intracellular glutathione levels have a strong influence on the T cell system . A study of healthy human subjects revealed that persons with intracellular glutathione levels of 20-30 nmol/mg protein had significantly higher numbers of CD4+ T cells than persons with either lower or higher glutathione levels. Persons who moved during a 4-week observation period from the optimal to the suboptimal range (10-20 nmol/mg) experienced, on the average, a 30% decrease in CD4+ T cell numbers. This decrease was prevented by treatment with N-acetyl-cysteine (NAC). NAC caused this relative increase of CD4+ T cell numbers in spite of decreasing glutathione levels and not by increasing the glutathione level. Our studies suggest that the immune system may be exquisitely sensitive not only against a cysteine and glutathione deficiency but also against an excess of cysteine." (48).

"In 1989, Eck et al. measured the level of acid soluble-SH groups in plasma and the intracellular concentration of reduced glutathione (GSH) in peripheral blood mononuclear cells (PBMC) and monocytes in HIV-infected patients: both were found to be significantly decreased. Following the above report, Buhl et al. (1989) determined the glutathione concentration (reduced, oxidised and total) in plasma and lung epithelial lining fluid of symptom-free HIV seropositive individuals: in both tissues, both the reduced and total GSH concentration was found to be significantly decreased." (69)

"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" (53)

"Purified reduced glutathione was delivered by aerosol to HIV seropositive individuals (n = 14) and the glutathione levels in lung epithelial lining fluid were compared before and at one, two, and three hours after aerosol administration. RESULTS--Before treatment total glutathione concentrations in the epithelial lining fluid were approximately 60% of controls. After three days of twice daily doses each of 600 mg reduced glutathione, total glutathione levels in the epithelial lining fluid increased and remained in the normal range for at least three hours after treatment. Strikingly, even though > 95% of the glutathione in the aerosol was in its reduced form, the percentage of oxidised glutathione in epithelial lining fluid increased from 5% before treatment to about 40% three hours after treatment, probably reflecting the use of glutathione as an antioxidant in vivo. No adverse effects were observed." (53) ."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".(53)

"Recently, orally given NAC has been shown to enhance the levels of GSH in the liver, in plasma, and notably in the bronchoalveolar lavage fluid. Rescue of GSH through NAC needs to be appreciated as an independent treatment modality for an array of different disease, all of which have one feature in common: pathogenetically relevant loss of GSH." (70). "These data suggest that N-acetylcysteine given by mouth is rapidly deacetylated to cysteine, with resulting increases in the concentrations of cysteine in plasma and of reduced glutathione in plasma and the airways, which thus temporarily increase the antioxidant capacity of the lung." (70b).

"The number of lung metastases decreased sharply when B16-F10 murine melanoma cells, injected i.v. into nude mice, were pre-treated with NAC and resuspended in medium supplemented with 10 mM NAC. In other experiments NAC was given in drinking water, starting 48-72 hr before subcutaneous inoculation of either B16-F10 cells or of their highly metastatic variant B16-BL6, or intramuscular injection of LLC cells. In all experiments NAC treatment decreased the weight of the locally formed primary tumor and produced a dose-related delay in tumor formation. Spontaneous metastasis formation by B16-F10 and B16-BL6 tumors was slightly yet significantly reduced by oral administration of NAC. However, this was not observed for Lewis lung tumors. These data indicate that NAC affects the process of tumor-cell invasion and metastasis, probably due to inhibition of gelatinases by its sulfhydryl group, with the possible contribution of other mechanisms, including the potent antioxidant activity of this thiol."(71)

"A study evaluated the critical role of glutathione (GSH), (an endogenous antioxidant) in silica-induced oxidative stress, cytotoxic (cell toxicity), and genotoxicity (DNA damage that may cause mutation or cancer) in rat macrophages (immune cells). The intracellular GSH content was modulated by N-acetylcysteine, a GSH precursor, and buthionine sulfoximine, a GSH synthesis inhibitor. It was found that the silica-induced stress led to a dose- and time-dependent decrease in GSH content in the macrophages. N-acetylcysteine (NAC) increased intracellular GSH level and protected against silica-induced free radical formation, lactate dehydrogenase leakage, and DNA strand breaks in macrophages" (72).

"I-152 is a prodrug of NAC and MEA with potent pro-GSH effects in human macrophages, astrocytes and lymphocytes. This molecule could be of interest in HIV infection in respect to its antioxidant and anti-HIV activities, but also in other diseases to counteract oxidative stress, that is, in.ammation, cardiovascular diseases, and neurodegenerative diseases. It is now well established that antioxidants could be valuable in various clinical situations in which oxidative stress plays a role in pathological disorders (e.g., viral diseases, cardiovascular diseases, in.ammation, cancer, neurological diseases, septic shock, etc.).

Hence, our interest in this study was in the design of new potent antioxidant molecules. In this respect, we would like to report herewith on an NAC/MEA13 conjugate compound, I-152, which seems to be a highly potent antioxidant by increasing the glutathione (GSH) content in various cell lines" (50).

"In conclusion, I-152 is a potent pro-GSH compound as compared to NAC, MEA or other molecules of the same family. These pro-GSH e.ects are observed in different cell lines suggesting the high potential of this new molecule. The biological interest of I-152 is confirmed by the significant decrease of HIV replication in MDMs, in absence of cytotoxicity. Altogether, these data suggest that I-152 could be of great interest in pharmacology but also in cosmetology or other domains involving oxidative stress.(50)

"Reduced apoptosis is associated to cancer development. Agents able to restore the programmed cell death responsiveness of cancer cells are foreseen as potential effective cancer therapies. In this study, we report that a glutathione-S-derivative, S-acetyl-glutathione (Sag), induces significant apoptosis in three human lymphoma cell lines,including Daudi, Raji and Jurkat cells while it had no or little effect on either Hut-78 lymphoma cells or the normal B lymphocytes."(59)

"This study demonstrates that (1) exogenously added GSH promotes the survival of IL-2-deprived activated T cells by influencing the GSH content of the cells; (2) intrinsic intracellular GSH levels are critical for activated T-cell survival; and (3) WI38-promoted survival of activated T cells leads to a concomitant rise in the intracellular GSH level of the cells, associated with factor(s) of greater than 30 kD. Taken together, these observations implicate GSH as a possible mediator in fibroblast-enhanced survival of activated T cells.

The apoptosis induced in activated T cells by the withdrawal of IL-2 in vitro is associated with a decrease in Bcl-2 expression12 (this study). As we have previously demonstrated, the continued presence of cytokines such as IL-2, IL-4, IL-7, and IL-15 (all of which signal via the -chain of the IL-2 receptor) promotes the survival of these cells via up regulation of Bcl-2 and subsequent cell proliferation.13 In contrast, fibroblast-promoted T-cell survival appears to be independent of Bcl-2, as Bcl-2 is not re-expressed in the rescued cells.12 This is also true for activated T cells rescued from apoptosis by the addition of exogenous GSH in vitro (this study)." (49).

"The aim of this study was to assess the serum viral load, CD4, CD8, lymphocyte count and hematocrit at the beginning of antiretroviral therapy in individuals who were supplemented with N-acetylcysteine (NAC). Twenty volunteers participated in this double-blind, placebo-controlled 180-day study. Ten participants received 600 mg of NAC per day (NAC group) and the other ten serving as a control group received placebo. The above mentioned parameters were determined before treatment, and after 60, 120 and 180 days. In NAC-treated patients hematocrit remained stable and an increase in CD4 cell count took place earlier than that in the control group."(54)

"To determine the therapeutic effect of sulfur amino acid supplementation in HIV infection we randomized 40 patients with antiretroviral therapy (ART; study 1) and 29 patients without ART (study 2) to treatment for 7 months with N-acetyl-cysteine or placebo at an individually adjusted dose according to a defined scheme. The main outcome measures were the change in immunological parameters including natural killer (NK) cell and T cell functions and the viral load. Both studies showed consistently that N-acetyl-cysteine causes a marked increase in immunological functions and plasma albumin concentrations. The effect of N-acetyl-cysteine on the viral load, in contrast, was not consistent and may warrant further studies. 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 treatment may be recommended for patients with and without ART. 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."(56)

Anti wasting therapies including: anti oxidants, NAC, Cystein rich undenurtured whey proteins, combination of L-Glutamine, metobolite of amino acid leucine HMB, L-Arginine.

"Nutritional problems have been a part of the clinical aspects of AIDS from its earliest recognition as a new disease" (37, 41). "In fact, in many AIDS patients, death seams to be determined more by the individualÕs nutritional status than by any particular opportunistic infection. This is, when wasting of lean body mass approaches 55% of normal for age, sex, and height, death is imminent regardless of the forces resulting is such profound malnutrition" (37, 41). Furthermore, the severity of the clinical manifestations of AIDS is proportional to the degree of the nutritional deficiencies (44-47)."(20).

"Macronutients are related to wasting and energy balance in HIV-infected patients, while micronutrients play different roles in immune function". (48) (20)

"Wasting, particularly loss of lean body mass, is associated with early mortality (68,69) and susceptibility to opportunistic infections (48,69). In a case control study nested within a follow up study, HIV-positive IV drug users with wasting (more than 10% loss of weight from baseline to last visit before death; mean follow-up, 2.4 years) had an approximately 8 fold higher risk of mortality compared with controls, after adjusting for CD4 cell counts". (48,55) (20).

"Higher mortality has been associated with low serum albumin (48,70). Low lean body mass index and high plasma levels of C-reactive proteins were also significant predictors of mortality among HIV-positive individuals followed for 42 months (48,71). Serum albumin and hemoglobin levels are also predictors of prognosis in HIV-positive children (48,72). Micronutrient deficiencies in HIV-positive individuals are associated with faster progression to AIDS". (73)(20)

"Undernutrition is a frequent complication of evolutive and chronic HIV (human immunodeficiency virus) infection characterized by bodyweight loss and changes in body composition. The Centers for Disease Control and Prevention define AIDS wasting as involuntary loss of more than 10% of body weight, plus more than 30 days of either diarrhea, or weakness and fever. Wasting syndrome has been considered as a case definition of the AIDS disease since 1987. Wasting syndrome is clearly linked to disease progression and death. Despite the progress under the era of highly active antiretroviral therapy (HAART), wasting is still a problem for people with AIDS. A small part of the weight lost is fat. More important is the loss of "lean body mass", which is mostly muscle" (32)

"Severe weight loss in HIV is associated with decreased length of survival. It is unclear whether mild weight loss is associated with an increased risk of death or opportunistic complications of HIV".(26) "Among those who lost 5% to 10% of their body weight, the relative risk of individual opportunistic complications increased significantly, including Pneumocystis carinii pneumonia (PCP) (1.61; p < .01), cytomegalovirus (CMV) (2.33; p < .001), and Mycobacterium avium complex (MAC) (1.81; p < .01). As little as 5%t weight loss over a 4-month period is associated with increased risk of death and opportunistic complications in HIV. A weight loss of 5% to 10% is also associated with an increased risk of individual opportunistic complications."(26)

"Survivors showed significantly larger initial body cell mass values and higher initial serum albumin levels compared with nonsurvivors, whereas CD4+ lymphocyte counts, disease complications, and medication were all similar in both groups. Kaplan-Meier analyses revealed a significantly prolonged survival in patients with a body cell mass > 30% of body weight or serum albumin levels exceeding 30 g/L. Factor analyses indicated that the parameters of nutritional state were independent from each other and from CD4+ lymphocyte counts. Malnutrition occurs frequently during HIV infection and increases with disease progress. It strongly predicts patient survival independent of CD4+ lymphocyte counts." (30)

"Weight loss and wasting have long been established as strong predictors of mortality in HIV-infected patients. Today, despite the effectiveness of highly active antiretroviral therapy (HAART), there is evidence that HIV-related wasting is still an important comorbidity in many patients"(25)

"In analyses examining the parameters separately and together in the same model, weight loss emerged as the strongest independent predictor of mortality. Weight loss of >or=10% from baseline or the previous visit was significantly associated with a four- to sixfold increase in mortality compared with maintenance or gaining of weight. Even one episode of weight loss of >or=3% from baseline or >or=5% from the previous visit was predictive of mortality. In summary, despite the apparent benefits of HAART use on HIV-related survival, weight loss remains an independent predictor of mortality."(25)

"Lean body mass (adjusted to height), body cell mass, CD4 count, albumin, prealbumin, and C-reactive protein (CRP) were all significant predictors. Age, stage of disease, number of previous opportunistic infections, and antiviral therapies were not associated with a change in survival. With the multivariate model, only CD4 counts, lean body mass/height squared, and CRP remained significant independent predictors of survival after controlling for other factors."(31)

"Tissue wasting often occurs during human immunodeficiency virus infection and acquired immune deficiency syndrome. While weight-loss in the human immunodeficiency virus-infected individual can be seen as an isolated symptom, catabolism during acquired immune deficiency syndrome is usually associated with complications such as diarrhea, malabsorption, fever and secondary infection. Glutamine is an amino acid central to many important metabolic pathways and recent findings suggest that glutamine depletion may explain the progression of tissue wasting during human immunodeficiency virus infection."(22).

"The plasma of these mice showed decreased albumin and increased glutamate levels, which are typically found in practically all catabolic conditions. Skeletal muscles from tumor-bearing mice were found to have an abnormally low mitochondrial respiratory chain activity (mito.RCA) and significantly decreased glutathione (GSH) levels."(62)

"A common complication in malignant diseases is the massive loss of skeletal muscle mass (cachexia; 1 , 2). A similar process is seen in old age (3 , 4) and in patients with sepsis, trauma (1 , 5 , 6) , or certain infectious diseases, including HIV infection (7) . The mechanism of this phenomenon is still poorly understood. Indirect evidence suggests, however, that the mitochondrial oxidative energy metabolism may be severely compromised in the skeletal muscle tissue relatively early in the catabolic process. A high rate of glycolytic activity and lactate production is commonly seen in the skeletal muscle tissue in practically all catabolic conditions, including cancer (8 , 9) , burn injuries (10) , and sepsis (11) . Importantly, it was found even in well-nourished cancer patients, i.e., relatively early in the catabolic process (12) . Because the glycolytic metabolism is normally suppressed by ATP generated by the mitochondrial oxidative energy metabolism, the high glycolytic activity suggests that the capacity of the mitochondrial energy metabolism is too weak to meet the cellular demand for ATP. An abnormally low ATP level has been demonstrated already in patients with sepsis (13) , and a decreased phosphocreatine level has been found in the skeletal muscle of cachectic and precachectic SIV3 -infected macaques (14) ." (62)

"NAC has also been proposed for the treatment of HIV infection with the aim to reconstitute the abnormally low plasma cystine, glutamine, and arginine levels."35,57,58

In contrast to cancer patients and elderly subjects, HIV-infected persons frequently have cystine/thiol ratios that are lower than normal (H.P. Eck, R. Breitkreutz, W. Dršge, unpublished observation, 1988-1998)." (62). "LIKE APOPTOTIC cell death, senescence and wasting are largely autonomous and biologically meaningful processes associated with an increased probability of death. The hallmarks of these processes include the massive loss of body cell mass (bcm) and muscle function, decreased resistance to infections, frailty (increased probability of disability), and organ failure.1-9 A biochemical correlate of senescence and a quantitative measure of cachexia is the decrease in the plasma albumin level.10-15 Wasting is a common phenomenon in malignancies,2-5 sepsis, trauma,6 and certain infectious diseases including human immunodeficiency virus (HIV) infection.7,8" . (62) "One of the prevailing hypotheses states that senescence may result from the accumulation of oxidative damage20-22 and that dietary antioxidants may slow the degenerative process.20,22,23 In support of this paradigm, vitamin E was shown to ameliorate age-related health problems,24 and certain age-related degenerative changes were even found to be reversed by antioxidant treatment.22,23" (62) .

"In this report we now show (1) that senescence and wasting are associated with an easily demonstrable change in the redox state of the blood plasma, and (2) that important consequences of changes in the redox state can be shown in human subjects within a few weeks or months. In view of these relatively short observation periods, our findings may provide, for the first time, a quantitative guideline for a redox-oriented prophylactic therapy." (62)

"The mitochondrion is known to be exquisitely sensitive against reactive oxygen intermediates (15 , 16) but generates superoxide radicals and hydrogen peroxide, especially if its transmembrane potential (i.e., the energy state) is low (17, 18, 19) . This generates a potentially vicious circle unless contained by protective mechanisms. In addition, mitochondria were found to produce NO (20 , 21) , which is also potentially damaging for mitochondria (21, 22, 23, 24) and has been implicated in another animal model of cachexia (24) . It, therefore, makes sense that mitochondria require normally adequate concentrations of antioxidants and radical scavengers, such as GSH (25 , 26) . Spermine is another important scavenger of ROIs (27) that was found to exert protective effects on mitochondria (28, 29, 30) . Among other claims, it was claimed that spermine strongly inhibits the induction of mitochondrial nitric oxide synthase (31) . Here, therefore, we investigated mito.RCA in the skeletal muscle tissue from tumor-bearing and normal mice and determined the effects of the GSH precursor cysteine, the spermine precursor ornithine, and the NO precursor arginine.". (62). "These changes include, among others, a conspicuous increase in the plasma glutamate level (33) , which is similarly found in cancer patients (1 , 35 , 36) , HIV/SIV infection (37 , 38) , non-insulin-dependent diabetes mellitus (39) , amyotrophic lateral sclerosis (40) , and old age (39) . Even in healthy human subjects, episodes with elevated plasma glutamate levels were significantly correlated with a decrease in body cell mass (41) . A study on lung cancer patients revealed that plasma glutamate levels were significantly correlated with mortality (36)." (62). "In addition, the elevated plasma glutamate levels have been shown to be associated with a decreased muscular uptake of glutamate and a corresponding decrease in i.m. glutamate and GSH levels (33 , 39 , 42) .."(62). "The decrease in albumin was found to be strongly correlated with a decrease in body cell mass and with the probability of survival (reviewed in Refs. 43, 44, 45)." (62). "The hypothesis of a cause/effect relationship between the decrease in mito.RCA and the change in the GSSG/GSH ratio and the plasma redox state (cystine/thiol ratio; Fig. 10 ) is supported by the strong correlation (Fig. 2)." (62). "Substantially decreased i.m. glutamate levels have been found not only in our murine model of cachexia but also in patients with sepsis or trauma (60 , 61) and in cachectic and precachectic SIV-infected macaques (42) . In the SIV study as well as in our tumor-bearing mice, the decreased glutamate levels were shown to be associated with decreased GSH levels (see Fig. 4A).". (62). "A role of NO in cachexia was suggested recently by studies on a tumor necrosis factor-induced murine model of cachexia (24) . In this model, skeletal muscle wasting was prevented by treatment with antioxidants or with the NO synthase inhibitor nitro-L-arginine (24)" .(62)

"Reactive oxygen and nitrogen intermediates are important antimicrobial defense mechanisms of macrophages and other phagocytic cells. While reactive nitrogen intermediates have been shown to play an important role in tuberculosis control in the murine system, their role in human disease is not clearly established. Glutathione, a tripeptide and antioxidant, is synthesized at high levels by cells during reactive oxygen intermediate and nitrogen intermediate production. Glutathione has been recently shown to play an important role in apoptosis and to regulate antigen-presenting-cell functions. Glutathione also serves as a carrier molecule for nitric oxide, in the form of S-nitrosoglutathione. Previous work from this laboratory has shown that glutathione and S-nitrosoglutathione are directly toxic to mycobacteria" (52)

"Wasting of muscle mass, commonly present in patients with chronic obstructive pulmonary disease, is a complex process involving changes in the control of intermediary metabolism as well as in muscle cell status. Although research exploring intermediary metabolism in chronic obstructive pulmonary disease is still in its infancy, there is an increased interest in a potential role for amino acids in modulating muscle anabolism. This review aims at summarizing and critically evaluating the available clinical studies examining alterations in amino acid profile in plasma and skeletal muscle of patients with chronic obstructive pulmonary disease.

All studies show pronounced alterations in plasma and muscle amino acid status in patients with chronic obstructive pulmonary disease but no consistent 'disease specific' pattern for most amino acids. Variability is likely influenced by the heterogeneity of the disease with respect to lung function and nutritional state. Nevertheless, general consistency exists in chronic obstructive pulmonary disease with respect to (1) a reduced plasma branched-chain amino acid level, and (2) a decreased muscle glutamate concentration. Alterations in branched-chain amino acid metabolism appear to be influenced by the degree of muscle wasting, while the reduction in muscle glutamate is related to the diffusing capacity as a hallmark of emphysema. The reduction in glutamate status is associated with reduced muscle glutathione levels and appears to be linked to enhanced glycolysis as evidenced from an accelerated increase in plasma lactate."(42)

"Up to 20% of patients with AIDS have abnormal intestinal permeability (IP). Glutamine seems to play an important role in preventing the increase in IP and loss of intestinal mucosal mass associated with total parenteral nutrition, and may be superior to glucose for oral rehydration in the setting of intestinal infection. This study was designed to see if supplemental glutamine could alter the abnormal IP of AIDS." (36).

"All patients complied with the therapy and there were no dropouts or reported side effects. The results showed less worsening of IP with the 4 g/day dose, compared with placebo. At the 8 g/day dose, there was stabilization of IP and improved absorption of mannitol. Intestinal morphology and inflammation did not change in any group. CONCLUSIONS: These results, although not significant, suggest a trend towards improved IP and enhanced intestinal absorption with glutamine. Glutamine doses of at least 20 g/day may be necessary to improve IP. We recommend further studies at higher doses and for longer durations." (36) .

"Supplementation of several amino acids has been suggested as a method for reducing weight loss among HIV-infected individuals. A combination of three amino acids known as HMB/Gln/Arg-beta-hydroxy-beta-methylbityrate (HMB), a metabolite of leucine, L-glutamine (Gln), and L-arginine (Arg), given for 8 weeks to patients with HIV-associated wasting, resulted in significant weight gain for patients in the treatment arm compared with those receiving placebo [306]" (48). (20)

"The current study was designed to examine whether a combination of three nutrients, consisting of beta-hydroxy-beta-methylbutyrate (HMB), a metabolite of leucine, L-glutamine (Gln) and L-arginine (Arg), each of which has been previously shown to slow muscle proteolysis, could synergistically alter the course of muscle wasting in patients with established acquired immunodeficiency syndrome (AIDS)."(25)

"The subjects were randomly assigned in a double-blind fashion to receive either placebo containing maltodextrin or the nutrient mixture (HMB/Arg/Gln) containing 3 g HMB, 14 g L-glutamine, and 14 g L-arginine given in two divided doses daily for 8 weeks. Body weights (BW) were recorded weekly and lean body mass (LBM) and fat mass (FM) were measured by air displacement plethysmography and by a single computerized tomography (CT) slice through the thigh at 0, 4, and 8 weeks. RESULTS: Forty-three subjects completed the 8-week protocol, (placebo, n = 21; HMB/Arg/Gln, n = 22). At 8 weeks, the subjects consuming the HMB/Arg/Gln mixture gained 3.0 +/- 0.5 kg of BW while those supplemented with the placebo gained 0.37 +/- 0.84 kg (p = .009). The BW gain in the HMB/Arg/Gln-treated subjects was predominantly LBM (2.55 +/- 0.75 kg) compared with the placebo-supplemented subjects who lost lean mass (-0.70 +/- 0.69 kg, p = .003). No significant change in FM gain was observed (0.43 +/- 0.83 kg for the group receiving HMB/Arg/Gln and 1.07 +/- 0.64 kg for the group receiving the placebo, p > .20). Similar percentage changes in muscle mass and fat mass were observed with CT scans. Immune status was also improved as evident by an increase in CD3 and CD8 cells and a decrease in the HIV viral load with HMB/Arg/Gln supplementation. CONCLUSIONS: The data indicate that the HMB/Arg/Gln mixture can markedly alter the course of lean tissue loss in patients with AIDS-associated wasting." (25)

In a clinical study, Juven-supplemented subjects gained an average of 5 1/2 pounds over 8 weeks (p<.005). Placebo-supplemented subjects lost an average of just over 1 pound.

Another successful study using HMB/Arg/Gln to stop and reverse wasting.

"Thirty-two patients (14 control, 18 HMB/Arg/Gln) were evaluated at the 4-week visit. The patients supplemented with HMB/Arg/Gln gained 0.95 ± 0.66 kg of body mass in 4 weeks, whereas control subjects lost 0.26 ± 0.78 kg during the same time period. This gain was the result of a significant increase in FFM in the HMB/Arg/Gln-supplemented group (1.12 ± 0.68 kg), whereas the subjects supplemented with the control lost 1.34 ± 0.78 kg of FFM (P = 0.02). The response to 24-weeks of supplementation was evaluated by an intent-to-treat statistical analysis. The effect of HMB/Arg/Gln on FFM increase was maintained over the 24 weeks (1.60 ± 0.98 kg; quadratic contrast over time, P <0.05). There was no negative effect of treatment on the incidence of adverse effects or quality of life measures." (64)

Conclusions: The mixture of HMB/Arg/Gln was effective in increasing FFM of advanced (stage IV) cancer. The exact reasons for this improvement will require further investigation, but could be attributed to the observed effects of HMB on slowing rates of protein breakdown, with improvements in protein synthesis observed with arginine and glutamine. (64)

"Tissue wasting often occurs during human immunodeficiency virus infection and acquired immune deficiency syndrome. While weight-loss in the human immunodeficiency virus-infected individual can be seen as an isolated symptom, catabolism during acquired immune deficiency syndrome is usually associated with complications such as diarrhea, malabsorption, fever and secondary infection. Glutamine is an amino acid central to many important metabolic pathways and recent findings suggest that glutamine depletion may explain the progression of tissue wasting during human immunodeficiency virus infection."(22)

"This study assessed the value of whey protein, a milk supplement, to prevent severe weight loss in children with AIDS." (23)"None of the children experienced any toxicity (side effects) such as diarrhea, vomiting or milk intolerance. All of them gained weight, between 3.2% and 18% from their starting weight. Eight demonstrated improvements in growth parameters, such as in tricep skinfolds, with mid-arm muscle circumference increasing from +1.2% to +25% independently of energy intake. No changes were found in CD4 cell count, but two children experienced a significant increase in CD8 cell count."(23)

"Conclusions: Whey protein is very well-tolerated in children with AIDS, and it was shown to improve nutrition and growth in a subgroup of patients." (23)

"HIV infection is characterized by an enhanced oxidant burden and a systemic deficiency of the tripeptide glutathione (GSH), a major antioxidant. The semi-essential amino acid cysteine is the main source of the free sulfhydryl group of GSH and limits its synthesis. Therefore, different strategies to supplement cysteine supply have been suggested to increase glutathione levels in HIV-infected individuals. The aim of this study was 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 a prospective double blind clinical trial, 30 patients (25 male, 5 female; mean age (± SD) 42 ± 9į8 years) with stable HIV infection (221 ± 102 CD4 + lymphocytes L1) were randomized to a supplemental diet with a daily dose of 45 g whey proteins of either Protectamin (Fresenius Kabi, Bad Hamburg, Germany) or Immunocal (Immunotec, Vandreuil, Canada) for two weeks. Plasma concentrations of total, reduced and oxidized GSH, superoxide anion (O2-) release by blood mononuclear cells, plasma levels of TNF- and interleukins 2 and 12 were quantified with standard methods at baseline and after therapy. Results Pre-therapy, plasma GSH levels (Protectamin: 1į92 ± 0į6 M; Immunocal: 1į98 ± 0į9 M) were less than normal (2į64 ± 0į7 M, P = 0į03). Following two weeks of oral supplementation with whey proteins, plasma GSH levels increased in the Protectamin group by 44 ± 56% (2į79 ± 1į2 M, P = 0į004) while the difference in the Immunocal group did not reach significance (+ 24į5 ± 59%, 2į51 ± 1į48 M, P = 0į43). Spontaneous O2- release by blood mononuclear cells was stable (20į1 ± 14į2 vs. 22į6 ± 16į1 nmol h1 106 cells, P = 0į52) whereas PMA-induced O2- release decreased in the Protectamin group (53į7 ± 19 vs. 39į8 ± 18 nmol h1 106 cells, P = 0į04). Plasma concentrations of TNF- and interleukins 2 and 12 (P > 0į08, all comparisons) as well as routine clinical parameters remained unchanged. Therapy was well tolerated."

Conclusion: "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."(47)

"Loss of body cell mass, the active functioning tissue of the body, commonly occurs in patients with human immunodeficiency virus (HIV) infection, and the extent of wasting is related to the length of survival"(29) "We evaluated the anabolic role of the amino acid L-glutamine (GLN) and antioxidants in a double-blind, placebo-controlled trial in 26 patients with > 5% weight loss since disease onset."(29)

"The GLN-antioxidant group gained 1.8 kg in body cell mass, whereas the control group gained 0.4 kg (P = 0.007). Intracellular water increased in the GLN-antioxidant group but not in the control group. In conclusion, GLN-antioxidant nutrient supplementation can increase body weight, body cell mass, and intracellular water when compared with placebo supplementation. GLN-antioxidant supplementation provides a highly cost-effective therapy for the rehabilitation of HIV+ patients with weight loss." (29)

"The most important redox buffers in skeletal muscle tissue and blood plasma, i.e. glutathione and albumin, respectively, are significantly decreased in different models of cachexia. Treatment with N-acetyl cysteine, i.e. a thiol-containing antioxidant, was found to increase the plasma albumin level and to ameliorate the loss of body cell mass in cancer patients and healthy individuals. The treatment of HIV infection with N-acetyl cysteine, in contrast, serves mainly as a tool to ameliorate the physiological and immunological consequences of the virus-induced cysteine deficiency." (1b)

"On the basis of numerous animal experiments, a pilot study was undertaken to evaluate the effect of undenatured, biologically active, dietary whey protein in 3 HIV-seropositive individuals over a period of 3 months. Whey protein concentrate was prepared so that the most thermosensitive proteins, such as serum albumin which contains 6 glutamylcysteine groups, would be in undenatured form. Whey protein powder dissolved in a drink of the patient's choice was drunk cold in quantities that were increased progressively from 8.4 to 39.2 g per day. Patients took whey proteins without adverse side effects. In the 3 patients whose body weight had been stable in the preceding 2 months, weight gain increased progressively between 2 and 7 kg, with 2 of the patients reaching ideal body weight. Serum proteins, including albumin, remained unchanged and within normal range, indicating that protein replenishment per se was not likely the cause of increased body weight. The glutathione content of the blood mononuclear cells was, as expected, below normal values in all patients at the beginning of the study. Over the 3-month period, glutathione levels increased in all 3 cases. In conclusion, these 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. This pilot study will serve as a basis for a much larger clinical trial." (63)

"All this argues in favour of oxidation as being a critical factor in the pathogenesis of AIDS and HIV expression." (69)

This is more than just an academic issue, what we have is an ongoing violation of the health rights and well being of all HIV positive people. Thank you for your attention. Best Wishes.

Yours sincerely

John Kirkham and James Whitehead
E-mail :


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25. Acquired Immune Defic Syndr. 2002 Oct 1;31(2):230-6. : Weight loss and survival in HIV-positive patients in the era of highly active antiretroviral therapy.Tang AM, Forrester J, Spiegelman D, Knox TA, Tchetgen E, Gorbach SL. Department of Family Medicine and Community Health, Tufts University School of Medicine, Boston, MA 02111, USA.
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27. Antioxidant Nutrients and AIDS: Exploring the Possibilities Interview With Dr. Luc Montagnier Interviewed By Richard A. Passwater Ph.D. References: 1. M. S. Gottlieb and I. Pozalski, Morb. Mortal. Wk. Rept. CDC, 30:250-2 (June 5, 1981) 2. A. Friedman, Morb. Mortal. Wk. Rept., CDC, 30:305-8 (July 3, 1981) 3. F. Barre-Sinoussi et al., Isolation of a T-lymphotropic retrovirus from a patient at risk foracquired immune deficiency syndrome (AIDS), Science 220:868 (May 20, 1983) 4. M-L. Gougeon and L. Montagnier, Apoptosis in AIDS, Science 260:1269-70(May 28, 1993) 5. A. Blanchard and L. Montagnier, AIDS-associated mycoplasmas, Ann. Rev. Microbiol.48:687-712 (1994)
28. JAIDS Journal of Acquired Immune Deficiency Syndromes 2002; 31:S84-S88 . Neuroprotection in HIV-Positive Drug Users: Implications for Antioxidant Therapy. Gail Shor-Posner; Robert Lecusay; Guillermo Morales; Adriana Campa; Maria-Jose Miguez.
29. 1: 1999 Nov-Dec;15(11-12):860-4. Glutamine-antioxidant supplementation increases body cell mass in AIDS patients with weight loss: a randomized, double-blind controlled trial.
30. Glutamine-antioxidant supplementation increases body cell mass in AIDS patients with weight loss: a randomized, double-blind controlled trial.Shabert JK, Winslow C, Lacey JM, Wilmore DW. Comment in: Nutrition. 2000 Jan;16(1):71-3. Department of Obstetrics and Gynecology, Harvard Medical School, Boston, Massachusetts, USA.
30b. Clin Chem Lab Med. 2002 Dec;40(12):1329-33. Body composition and nutritional parameters in HIV and AIDS patients. Salomon J, de Truchis P, Melchior JC. Department of Infectious Diseases and Clinical Nutrition, Raymond Poincare University Hospital, Garches, France. <>
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32. Impact of Selenium Status on the Pathogenesis of Mycobacterial Disease in HIV-1-Infected Drug Users During the Era of Highly Active Antiretroviral Therapy. Journal of Acquired Immune Deficiency Syndromes 2002;29:169-173
33. AIDS Res Hum Retroviruses 1992 Jul;8(7):1249-53 .Glutathione and N-acetylcysteine suppression of human immunodeficiency virus replication in human monocyte/macrophages in vitro. Ho WZ, Douglas SD. Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia.
34. High Risk of HIV-Related Mortality Is Associated With Selenium Deficiency. Marianna K. Baum; Gail Shor-Posner; Shenghan Lai; Guoyan Zhang; Hong Lai; Mary Ann Fletcher; Howerde Sauberlich; J. Bryan Page JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY 1997;15:370-374
35. Mortality Risk in Selenium-Deficient HIV-Positive Children. Adriana Campa; Gail Shor-Posner; Fernando Indacochea; Guoyan Zhang; Hong Lai; Deshratn Asthana; Gwendolyn B. Scott; Marianna K. Baum *Center for Disease Prevention, Department of Psychiatry and Behavioral Sciences, Department of Pediatrics, and ±Department of Medicine, University of Miami School of Medicine, Miami, Florida, U.S.A.JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY 1999;20:508-513
36. Am J Gastroenterol 1998 Jun;93(6):972-5 Related Articles, Links
A double-blind placebo-controlled pilot study of glutamine therapy for abnormal intestinal permeability in patients with AIDS. Noyer CM, Simon D, Borczuk A, Brandt LJ, Lee MJ, Nehra V. Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
38. NAC delays age-associated memory impairment. Full source: BRAIN RESEARCH, 2000, Vol 855, Iss 1, pp 100-106
39. Hart AM, Terenghi G, Johnson M, Youle M - L-Acetyl Carnitine (LAC) Therapy Increases Cutaneous Innervation and Improves Symptoms in Antiretrovital Therapy Related HIV peripheral neuropathy. Abstract 7.2 First International Workshop on Clinical Pharmacology, 30-31 March 2000. Noordwijk, Netherlands.
40. Naisbitt DJ, Vilar FJ, Stalford AC et al. AIDS Res Hum Retroviruses 2000 Dec;16(18):1929-1938. Also HIV Treatment Bulletin Vol2 No2 March 2001 .
41. Antioxidants may head off AIDS dementia .United Press International - Friday, 11 May 2001 PHILADELPHIA, May 11 (UPI) -- If laboratory tests on cell cultures hold true for patients infected with HIV, a researcher believes he has found a way to delay or even prevent the dementia that often accompanies the later stages of AIDS. Dr. Avindra Nath, a neurologist with the University of Kentucky in Lexington, said Friday he has not only discovered the specific cellular activity that leads to dementia in patients with HIV, but has developed a way to prevent the activity in the laboratory using antioxidants. He presented his preliminary findings at American Academy of Neurology's 53rd Annual Meeting in Philadelphia. AEGiS is made possible through unrestricted grants from Boehringer Ingelheim, iMetrikus, Inc., John M. Lloyd Foundation, the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2001. This material is designed to support, not replace, the relationship that exists between you and your doctor.
42. Current Opinion in Clinical Nutrition and Metabolic Care 2003; 6(1):73-78
Altered amino acid metabolism in chronic obstructive pulmonary disease: new therapeutic perspective? Mari‘lle P.K.J. Engelen; Annemie M.W.J. Schols
43. Vol. 95, Issue 6, 3071-3076, March 17, 1998. Immunology Glutathione levels in antigen-presenting cells modulate Th1 versus Th2 response patterns. Proc Natl Acad Sci USA 1998 Mar 17;95(6): pp.3071-6]. Increasing glutathione levels helps reduce a Th2 dominance. Jeffrey D. Peterson*, Leonore A. Herzenberg dagger , Kristine Vasquez*, and Carl Waltenbaugh For full artical with graphs: yes#bottom
44. VIRUSMYTH HOMEPAGE. Taken from Continuum vol.3 no.5 Jan./Feb. 1996 .Reappraisal of the depletion of circulating CD4+ lymphocytes in HIV-carriers in transition to AIDS. Prof. Alfred Hžssig, Prof. Liang Wen-Xi and Dr. Kurt Stampfli. Continuum magazine (pdf) : .htm
45. Rhesus Monkey Simian Immunodeficiency Virus Infection as a Model for Assessing the Role of Selenium in AIDS Virus Infection as a Model for Assessing the Role of Selenium in AIDS Address correspondence and reprint requests to Dolph L. Hatfield, National Cancer Institute, National Institutes of Health, Building 37/Room 2D09, Bethesda, MD 20892, U.S.A.; e-mail:; or to Kathleen A. Clouse, Food and Drug Administration, Rockville, MD 20852, U.S.A.; e-mail: Manuscript received April 19, 2002; accepted September 4, 2002. JAIDS Journal of Acquired Immune Deficiency Syndromes 2002; 31(5):453-463. Xue-Ming Xu; *Bradley A. Carlson; †Tobias A. Grimm; †Joseph Kutza; ąMarla J. Berry; *Raul Arreola; †Karen H. Fields; *Ilanchezhian Shanmugam; ¤Kuan-Teh Jeang; ||Stephen Oroszlan; Gerald F. Combs, Jr.; #Preston A. Marx; **Vadim N. Gladyshev; †Kathleen A. Clouse; *Dolph L. Hatfield. Taken from the general forums section:
46. Eur J Clin Nutr. 1997 Apr;51(4):266-72. Related Articles, Links .Serum selenium, plasma glutathione (GSH) and erythrocyte glutathione peroxidase (GSH-Px)-levels in asymptomatic versus symptomatic human immunodeficiency virus-1 (HIV-1)-infection. Look MP, Rockstroh JK, Rao GS, Kreuzer KA, Barton S, Lemoch H, Sudhop T, Hoch J, Stockinger K, Spengler U, Sauerbruch T. Department of General Internal Medicine, University of Bonn, Germany.
47. European Journal of Clinical Investigation .Volume 31 Issue 2 Page 171 - February 2001
doi:10.1046/j.1365-2362.2001.00781.x . Oral supplementation with whey proteins increases plasma glutathione levels of HIV-infected patients. P. Micke, K. M. Beeh, J. F. Schlaak and R. Buhl. Pulmonary Division, III. Medical Department, Mainz University Hospital, D-455101 Mainz, Germany. Taken from post headed SWEET TASTING MEDICINE THAT WORKS in the Alternative Therapies section on start
48. FASEB J. 1994 Apr 1;8(6):448-51. Effect of glutathione depletion and oral N-acetyl-cysteine treatment on CD4+ and CD8+ cells. Kinscherf R, Fischbach T, Mihm S, Roth S, Hohenhaus-Sievert E, Weiss C, Edler L, Bartsch P, Droge W. Department of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
49. Blood, Vol. 89 No. 7 (April 1), 1997: pp. 2453-2460. Upregulation of Intracellular Glutathione by Fibroblast-Derived Factor(s): Enhanced Survival of Activated T Cells in the Presence of Low Bcl-2. By Helena Hyde, Nicola J. Borthwick, George Janossy, Michael Salmon, and Arne N. Akbar >From the Department of Clinical Immunology, Royal Free Hospital School of Medicine, London; and the Department of Rheumatology, Birmingham University Medical School, Birmingham, UK. Taken from post headed SWEET TASTING MEDICINE THAT WORKS in the Alternative Therapies section on start Go Here for full artical with Graphs /89/7/2453
50. Bioorganic & Medicinal Chemistry Letters 11 (2001) 1189Š1191 .NAC/MEA Conjugate: A New Potent Antioxidant Which Increases the GSH Levelin Various CellLines .Joe¬ l Oiry,a,* Patricia Mialocq,b Jean Y. Puy,a Philippe Fretier,b Pascal Clayette,b Dominique Dormontb and Jean L. Imbacha. Laboratoire de Chimie Organique Biomoléculaire de Synthèse, UMR 5625 CNRS-UM II, Universite« Montpellier II, Sciences et Techniques du Languedoc, place Euge`ne Bataillon, 34095 Montpellier Cedex 5, France. bService de Neurovirologie, CEA/DSV/DRM, CRSSA, EPHE, 60Š68 avenue de la Division Leclerc, BP 6, 92265 Fontenay aux Roses Cedex, France. Received 9 February 2001; revised 7 March 2001; accepted 7 March 2001 . Click here to read full artical with references: yes#bottom
51. 1: Crit Care Med. 2003 Apr;31(4):1042-7. Related Articles, Links. Detecting life-threatening lactic acidosis related to nucleoside-analog treatment of human immunodeficiency virus-infected patients, and treatment with L-carnitine. Claessens YE, Cariou A, Monchi M, Soufir L, Azoulay E, Rouges P, Goldgran-Toledano D, Branche F, Dhainaut JF. Medical Intensive Care Unit, Cochin Hospital, 27 rue du Faubourg Saint-Jacques, F-75679 Paris Cedex 14, France.
52. Infection and Immunity, April 2003, p. 1864-1871, Vol. 71, No. 4 0019-9567/03/$08.00+0 DOI: 10.1128/IAI.71.4.1864-1871.2003 Copyright © 2003, American Society for Microbiology. All Rights Reserved. Role of Glutathione in Macrophage Control of Mycobacteria
Vishwanath Venketaraman,1,2,3 Yaswant K. Dayaram,1,2,3 Amol G. Amin,1,2,3 Richard Ngo,1 Renee M. Green,1 Meliza T. Talaue,1,2,3 Jessica Mann,1,2,3 and Nancy D. Connell1,2,3* Department of Microbiology and Molecular Genetics,1 New Jersey Medical School National Tuberculosis Center, 2 Center for Emerging and Re-emerging Pathogens, UMDNJ-New Jersey Medical School, Newark, New Jersey 071033 .Received 3 July 2002/ Returned for modification 8 October 2002/ Accepted 14 January 2003 . Taken from post headed SWEET TASTING MEDICINE THAT WORKS in the Alternative Therapies section on
53. Thorax. 1993 Oct;48(10):985-9. Correction of glutathione deficiency in the lower respiratory tract of HIV seropositive individuals by glutathione.
54. HIV-Related Peripheral Neuropathy Improves with Oral L-Acetyl Carnitine By Harvey S. Bartnof, MD . Quotes from Michael Youle, MD, from the Royal Free Center for HIV Medicine in London, UK.
1. De Simone C and others. Carnitine depletion in peripheral blood mononuclear cells from patients with AIDS: effect of oral L-carnitine. AIDS. 1994 May;8(5):655-60.
2. Famularo G and others. Acetyl-carnitine deficiency in AIDS patients with neurotoxicity on treatment with antiretroviral nucleoside analogues. AIDS. 1997 February;11(2):185-90.
3. Famularo G and others. Carnitine stands on its own in HIV infection treatment. Archives of Internal Medicine. 1999 May 24;159(10):1143-4.
4. Hart AM, Youle M and others. Immunohistochemical quantification of cutaneous innervation in HIV-associated peripheral neuropathy: a study of L-acetyl carnitine therapy. Abstract and oral presentation 36 at the 3rd International Workshop on Salvage Therapy for HIV Infection; April 12-14, 2000; Chicago; Illinois and Antiviral Therapy 2000; 5 (Suppl. 2): 32.
5. McArthur J. Nerve growth factor for HIV-associated sensory neuropathy. Late Breaker abstract and oral presentation 12/32454 at the 12th World AIDS Conference; June 28-July 3, 1998; Geneva, Switzerland.
6. Shlay JC and others. Acupuncture and amitriptyline for pain due to HIV-related peripheral neuropathy: a randomized controlled trial. Terry Beirn Community Programs for Clinical Research on AIDS. Journal of the American Medical Association. 1998 November 11;280(18):1590-5.
7. Virmani MA and others. Protective actions of L-carnitine and acetyl-L-carnitine on the neurotoxicity evoked by mitochondrial uncoupling or inhibitors. Pharmacologic Research. 1995 December;32(6):383-9.
8. (No author listed). Acetyl-L-carnitine. Alternative Medicine Reviews. 1999 December; 4(6):438-41. Taken from post headed SWEET TASTING MEDICINE THAT WORKS in the Alternative Therapies section on start

55. Clin Chem Lab Med. 2002 May;40(5):452-5. Clinical Trial. Randomized Controlled Trial .PMID: 12113286 [PubMed - indexed for MEDLINE]
56. Journal of Molecular Medicine. Issue: Volume 78, Number 1 .Pages: 55 - 62
Improvement of immune functions in HIV infection by sulfur supplementation: Two randomized trials .Raoul Breitkreutz A1, Nicole Pittack , Carl Thomas Nebe A4, Dieter Schuster A3, JŸrgen Brust A3, Matthias Beichert A5, Volker Hack A1, Volker Daniel A6, Lutz Edler A7, Wulf Dršge A1 .A1 Deutsches Krebsforschungszentrum, Division of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany, e-mail:, Tel.: +49-6221-423706, Fax: +49-6221-423746 .A2 Medizinische Klinik I, 68167 Mannheim, Germany .A3 HIV-Schwerpunktpraxis, 68167 Mannheim, Germany .A4 Institut fŸr klinische Chemie, 68167 Mannheim, Germany .A5 Universitžts-Frauenklinik, 68167 Mannheim, Germany .A6 Institut fŸr Immunologie, Universitžt Heidelberg, 69120 Heidelberg, Germany .A7 Deutsches Krebsforschungszentrum, Biostatistics Unit, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
57. Blood, Vol. 91 No. 10 (May 15), 1998: pp. 3817-3824. Effect of L-Carnitine on Human Immunodeficiency Virus-1 Infection-Associated Apoptosis: A Pilot Study. By Sonia Moretti, Edoardo Alesse, Luisa Di Marzio, Francesca Zazzeroni, Barbara Ruggeri, Sonia Marcellini, Giuseppe Famularo, Seth M. Steinberg, Antonio Boschini, M. Grazia Cifone, and Claudio De Simone . Go here for link to full article with graphs: 1&ThreadID=1092872
58. Collection of Cell INTERNATIONAL JOURNAL OF ONCOLOGY 20: 69-75, 200269. S-acetyl-glutathione selectively induces apoptosis in humanlymphoma cells through a GSH-independent mechanismROBERTO LOCIGNO1, JOEL PINCEMAIL2, AUDREY HENNO1,GERNOT TREUSCH3and VINCENT CASTRONOVO11Metastasis Research Laboratory and 2Thoracic and Cardio-Vascular Surgery Department. Taken from post headed SWEET TASTING MEDICINE THAT WORKS in the Alternative Therapies section on : 203 has link to full article.
59. Antioxid Redox Signal. 2002 Jun;4(3):391-403. Related Articles, Links. L-carnitine reduces lymphocyte apoptosis and oxidant stress in HIV-1-infected subjects treated with zidovudine and didanosine. Moretti S, Famularo G, Marcellini S, Boschini A, Santini G, Trinchieri V, Lucci L, Alesse E, De Simone C. Department of Experimental Medicine, University of L'Aquila, Rome, Italy.
60. Clinical Immunology .Volume 92, Issue 1 , July 1999 , Pages 103. Acetyl--carnitine Administration Increases Insulin-like Growth Factor 1 Levels in Asymptomatic HIV-1-Infected Subjects: Correlation with Its Suppressive Effect on Lymphocyte Apoptosis and Ceramide Generation. Luisa Di Marzioa, Sonia Morettib, Simona D'Al˜a, Francesca Zazzeronia, Sonia Marcellinib, Camillo Smacchiac, Edoardo Alessea, M. Grazia Cifonea and Claudio De Simonea .a Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy. b Department of Infectious Diseases, University La Sapienza, Rome, Italy. c San Patrignano Medical Center, Rimini, Italy Received 11 September 1998; accepted 29 March 1999. Available online 2 April 2002.
61. (Journal of Leukocyte Biology. 2002;72:271-278.) © 2002 by Society for Leukocyte Biology. CD4 lymphocytes in the blood of HIV+ individuals migrate rapidly to lymph nodes and bone marrow: support for homing theory of CD4 cell depletion. Jenny J-Y. Chen*, Jason C. Huang, Mark Shirtliff*, Elma Briscoe, Seham Ali, Fernando Cesani, David Paar and Miles W. Cloyd*, Departments of * Microbiology & Immunology, Pathology, Nuclear Medicine, and Internal Medicine, University of Texas Medical Branch, Galveston .Correspondence: Miles W. Cloyd, Ph.D., Department of Microbiology and Immunology, Rt. 1070, The University of Texas Medical Branch, Galveston, TX 77555-1070. E-mail:
62. Cancer Research 59, 3527-3534, July 15, 1999] © 1999 American Association for Cancer Research. Tumor Biology. Differential Reconstitution of Mitochondrial Respiratory Chain Activity and Plasma Redox State by Cysteine and Ornithine in a Model of Cancer Cachexia. Alexej Ushmorov1, Volker Hack1 and Wulf Dršge2 Deutsches Krebsforschungszentrum, Division of Immunochemistry, D-69120 Heidelberg, Germany
63. Clin Invest Med. 1993 Jun;16(3):204-9. Whey proteins as a food supplement in HIV-seropositive individuals. Bounous G, Baruchel S, Falutz J, Gold P. Department of Surgery, Montreal General Hospital, Quebec.
64. The American Journal of Surgery. Volume 183, Issue 4, April 2002, Pages 471-479. Reversal of cancer-related wasting using oral supplementation with a combination of -hydroxy- -methylbutyrate, arginine, and glutamine. Patricia Eubanks May M.D. a, b, Annabel Barber M.D.b, James T. D'Olimpio M.D.c, Ann Hourihane, N.P.c and Naji N. Abumrad M.D.c.a Department of Surgery/112, Veterans Affair Medical Center, 1000 Locust St., Reno, NV 85920, USA. b Department of Surgery, University of Nevada School of Medicine, Reno, NV, USA. c Department of Surgery and Don Monti Division of Medical Oncology, North Shore University Hospital, Manhasset, NY, USA .Received 17 December 2001;  revised 10 January 2002.  Available online 18 April 2002.
65. Proceedings of the National Academy of Sciences, Vol 88, 1913-1917, Copyright © 1991 by National Academy of Sciences. Glutathione Deficiency Leads to Mitochondrial Damage in Brain. A Jain, J Martensson, E Stole, PAM Auld and A Meister
66. P. Arivazhagan, S. R. Panneerselvam, and C. Panneerselvam. Effect of DL-{alpha}-Lipoic Acid on the Status of Lipid Peroxidation and Lipids in Aged Rats. J. Gerontol. A Biol. Sci. Med. Sci., September 1, 2003; 58(9): B788 - 791. [Abstract] [Full Text] [PDF]
67. Blood, Vol. 92 No. 1 (July 1), 1998: pp. 59-67. The Redox State as a Correlate of Senescence and Wasting and as a Target for Therapeutic Intervention. By Volker Hack, Raoul Breitkreutz, Ralf Kinscherf, Helmut Ršhrer, Peter Bžrtsch, Friedemann Taut, Axel Benner, and Wulf Dršge. From the Division of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg; Onkologische Schwerpunktpraxis, Ihringen; the Department of Sports Medicine, University of Heidelberg, Heidelberg; the Department of Anesthesiology, University of Heidelberg, Heidelberg; and the Biostatistics Unit, Deutsches Kresbsforschungszentrum, Heidelberg, Germany.
68."We are Biological Hermophrodites in the Evolutionary Scheme of Life" Interview by Hans Jochim Ehlers (Raum + Zeit) with Heinrich Kremer, M.D., on AIDS and cancer. Raum + Zeit: Dr. Kremer, you have written a sensational book "Die stille Revolution der AIDS- und Krebsmedizin" ("The Silent Revolution in AIDS and Cancer Medicine"). First a question about what AIDS has to do with cancer?
69. Res. Immunol. 1992, 143, 145-148 . Oxidative Stress, HIV and AIDS. E. Papadopulos-Eleopulos (1) V.F. Turner (2) and J.M. Papadimitriou (3). (1) Department of Medical Physics, (2) Emergency Department and (3) Department of Pathology, (University of Western Australia), Royal Perth Hospital, Wellington St., Perth 6001 (Western Australia) VIRUSMYTH HOMEPAGE
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72. NAC boosts glutathione level in immune system. Full source: American Journal of Physiology-Lung Cellular and Molecular Physiology, 1999, Vol. 277, lss 4, pp L743-L748
73. J Hepatol. 2001 Dec;35(6):756-64. Related Articles, Links. Mechanism of azathioprine-induced injury to hepatocytes: roles of glutathione depletion and mitochondrial injury. Lee AU, Farrell GC. Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, 2145, Westmead, NSW, Australia.
74. Toxicology Volume 163, Issues 2-3 , 21 June 2001, Pages 153-162 . Thiram-induced cytotoxicity is accompanied by a rapid and drastic oxidation of reduced glutathione with consecutive lipid peroxidation and cell death. Catherine Cereser, a, b, Sophie Bogetb, Parviz Parvazc and AndrŽ Revol, b. a Laboratoire de Biochimie, UF Culture de Cellules, Centre Hospitalier Lyon-Sud, Chemin du Grand Revoyet, 69495 Pierre-BŽnite Cedex, France. b Laboratoire de Biochimie Endocrinienne et MolŽculaire, FacultŽ de Pharmacie, UniversitŽ Lyon I, 8 Avenue Rockefeller, 69373 Lyon Cedex 08, France.
75. Selected Highlights from the9th Conference on Retroviruses and Opportunistic InfectionsFebruary 24 - 28, 2002, Seattle, WA Symposium on T Cell Turnover and Thymic Function By Ross Hewitt, MD
76. From IMMUNOLOGYMDMA: Acute effects of ecstasy on T-cell numbers and functionSean Hosein, for Canadian AIDS Treatment Information ExchangeReferences: 1. Pacifici R., Zuccaro P., Farré M., et al. Effects of repeated doses of MDMA ("Ecstasy") on cell-mediated immune response in humans. Life Sciences 2001; 69:2931-2941. 2. Connor T.J., Connelly D.B. and Kelly J.P. Methylenedioxy-methamphetamine (MDMA; "Ecstasy") suppresses antigen specific IgG2a and IFN-gamma production. Immunology Letters 2001; 78(2): 67-73. Source: CATIE - Canadian AIDS Treatment Information Exchange.
77. Taken from drug company funded magazine Positive Nation UK.

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