How HIV-1 kills: Implications for the Treatment and Prevention of AIDS

Harold D. Foster

Abstract:

HIV-1 is parasitic. Since it encodes for glutathione peroxidase, as it replicates, its genetic needs cause it to deprive HIV-1 seropositive individuals of selenium, cysteine, glutamine and tryptophan, the four basic components of this selenoenzyme. Eventually this process causes severe deficiencies of each of these four nutrients. These deficiencies are responsible for the major symptoms of AIDS which include immune system collapse, muscle wasting, dermatitis, diarrhea and dementia. Associated pathogenic cofactors also are responsible for a variety of unique symptoms. Any treatment for HIV/AIDS must, therefore, include normalization of body levels of selenium, cysteine, glutamine and tryptophan.

Introduction

It is hypothesized that HIV-1 kills simply by replication, because as Taylor and coworkers have established, HIV-1 encodes for glutathione peroxidase. (1) This genetic characteristic ensures that as this virus replicates it competes with its host for the four basic components of this selenoenzyme: namely selenium, cysteine, glutamine and tryptophan. (2) It follows that unless supplements are added to the diet of HIV-1 seropositive individuals, this process must eventually, inevitably culminate in extreme shortages of these four substances, each of which will be accompanied by its own deficiency symptoms. It is argued here that AIDS is the end result of this multiple depletion process and that it can be treated most effectively by reversing all four of these nutrient deficiency states.

If this hypothesis is correct, HIV/ AIDS patients will be found to be deficient in selenium, cysteine, glutamine and tryptophan. As a result, supplementation with any one of these substances will reduce some, but not all, of their disease symptoms. The remainder of this article presents evidence that this is indeed the case.

Selenium Deficiency

Several studies have shown declining plasma selenium in individuals with HIV/AIDS. (3-5) Baum and coworkers, (3) for example, monitored 125 HIV-1seropositive drug using, men and women in Miami, Florida, establishing that depressed selenium plasma levels were a more accurate predictor of their mortality than were CD4 T cell counts. Similarly, 24 HIV-infected children were monitored for 5 years, during which time 50% died of HIV-related causes. (6) The lower their serum selenium levels, the more rapidly death occurred, indicating an association with faster disease progression.

Many of the symptoms associated with AIDS appear to be linked directly to selenium deficiency. This author (7) has argued that the fact that adults and children dying of AIDS display both depressed CD4 T cell counts and very depleted plasma selenium stores (3,6) is not coincidental. Rather, it provides evidence of the operation of a positive feedback system in which a fall in selenium triggers a reduction in the number of CD4 T cells because this trace element is essential for lymphocyte production. (8,9) This decline in CD4 T cells then allows other pathogens to thrive, a process which causes a further drop in serum selenium. (10) This downward spiral undermines the immune system and has been termed the "selenium -- CD4 T cell tailspin" by the author. (7)

A hypothyroid or low T3 syndrome also is well-established in patients with AIDS. (11,12) This low level of T3 (triiodothyronine) seen in AIDS patients also seems a logical consequence of selenium deficiency, since this trace element is required by the deiodinase enzyme that converts T4 (thyroxine) to T3. It has been further suggested that this selenium-related thyroid abnormality may be a factor in the AIDS wasting process. (13)

Although no clinical trials of the impact of selenium on AIDS patients have yet been conducted, some evidence of its value exists in the popular literature. In August 1987, for example, the Telegraph Sunday Magazine's cover published the photograph of a former patient with the headline "Four years ago this man was dying of AIDS. Now he is getting better." This newspaper supplement carried details of three former AIDS patients who had made remarkable recoveries by taking daily nutritional supplements that included 300 mcg of selenium.(14)

In addition, it has been suggested (7) that one of the major reasons HIV-1 infection is so low and almost static in Senegal, despite widespread unprotected sexual activity, is because the soils and food supply are unusually selenium enriched. In contrast, AIDS is now extremely common in those countries of Africa, such as Zaire, which are known to have very selenium deficient soils. The recently published Selenium World Atlas (15) used the incidence of HIV-positive populations as a surrogate measure of selenium deficiency in Africa, since knowledge of actual soil levels of this trace element is quite scarce. This argument by analogy was made on the advice of E.W. Taylor (15) who was the first to recognize that in Africa, HIV-1 was spreading most rapidly in selenium depleted regions. Interestingly, Cowgill (16) has shown that, in the United States, an inverse relationship also exists between soil selenium bioavailability and AIDS mortality rates, especially in the African American population.

Cysteine Deficiency

Several clinical studies and laboratory investigations have shown that HIV-infected patients display decreased plasma cysteine concentrations at all disease stages. (17,18) One of the major implications of this deficiency is an inability to produce adequate glutathione. Although glutathione is a peptide consisting of the three amino acids, glycine, glutamic acid and cysteine, it is usually the availability of the latter that controls its production. Since HIV-infected patients are deficient in cysteine, they are also typically short of glutathione. (19)

Cysteine inadequacy and, therefore, depressed blood glutathione levels are excellent indicators of AIDS-related mortality probability. AIDS patients with very low glutathione blood levels have been shown to have an estimated three-year survival probability of 20%, compared to a 60 to 80% survival rate in those maintaining more normal glutathione levels. (20) This is not surprising because glutathione acts as a nucleophilic scavenger and as an antioxidant in the event of tissue injury. Glutathione, therefore, has a major role as a protector of biological structures and functions. Depletion, as in paracetamol intoxication, is known to be extremely hazardous. (21) In addition, intracellular glutathione has a powerful impact on how well T- and B- lymphocyte cells function (22,23) and its availability also affects the production of macrophages, monocytes, and neutrophilis. It is apparent, therefore, that any cysteine deficiency leading to a decline in glutathione, will further damage the immune system in HIV-1 ser opositive patients. This is probably why HIV patients with low glutathione levels develop more secondary infections and cancers and have a higher mortality rate. (24) Indeed, there is evidence which suggests that glutathione supplementation can slow HIV-1 replication by inhibiting reverse transcriptase activity. (25,26)

Several studies (27,28) have demonstrated that cysteine supplementation (usually given as N-acetylcysteine) can replenish low glutathione in CD4 T cells and other immune-system components, presumably improving the ability to resist secondary pathogens and cancers.

Glutamine Deficiency

Glutamine deficiency is also a characteristic of AIDS. (29,30) This substance is a major nutrient for rapidly proliferating cells. As a result, it is of special significance in the digestive tract because it is necessary for intestinal cell proliferation, intestinal fluid/electrolyte absorption, and mitogenic response to growth factors. Glutamine deficiency also produces apoptosis. (31) It is not surprising, therefore, that many AIDS patients have abnormal intestine permeability, associated with digestive malfunction. (32) Noyer and colleagues, however, have demonstrated that an 8g/day glutamine supplementation can stabilize the intestinal permeability of patients with AIDS.

Muscle protein wasting occurs in HIV-infected individuals and is often an early indication of AIDS. Several studies (33-35) have demonstrated great benefit from glutamine supplementation. Indeed, Shabert and colleagues (29) were able to rehabilitate HIV-positive patients with such weight loss by glutamineantioxidant supplementation during a 12-week study. Similarly, Clark and coworkers (35) conducted a randomized, double-blind, placebo-controlled study involving sixty eight HIV-infected patients. This clearly demonstrated that beta-hydroxy beta-methylbutyrate, glutamine and arginine, given as a mixture, can markedly reduce lean tissue loss in patients suffering from AIDS-associated wasting.

Tryptophan Deficiency

Tryptophan is an essential amino acid that is needed for the biosynthesis of niacin, serotonin and proteins. (36) It has been shown that tryptophan is depressed in the serum and cerebrospinal fluids of patients with HIV-1 infection. (36,37) Indeed Werner and coworkers (38) demonstrated that in the sera of eleven male patients with advanced HIV infection, tryptophan levels were less than 50% of those in gender and age matched controls. Not surprisingly, niacin and serotonin levels in the serum of HIV/AIDS patients are also depressed. (39,40)

It has been argued that such niacin deficiencies resulting from, and combined with inadequate tryptophan, cause the development of many pellagra-like symptoms in AIDS. (36,39) Pellagra used to be a common disease which occurred in individuals who, for dietary reasons, lacked adequate niacin and tryptophan. As a result of these two deficiencies, such individuals could not produce adequate nicotinamide adenine dinucleotide and so developed pellagra. The symptoms of this disease were known as the four Ds, namely dermatitis, diarrhea, dementia and ultimately, if not treated effectively, death. (41) Interestingly, AIDS patients commonly experience such symptoms and are known to display inadequate levels of nicotinamide adenine dinucleotide. This can be reversed, at least in vitro, by the administration of nicotinamide. (42) Fuch and colleagues (43) have further demonstrated that there is a significant association between depressed serum tryptophan and polyneuropathy and dementia in HIV-1 seropositive patients. Thi s suggests that many of the neurologic/psychiatric symptoms seen in AIDS may be caused by the same nutrient deficiencies that cause pellagra, namely tryptophan and niacin.

Since tryptophan is also a necessary precursor of serotonin, the latter is always depressed when the former is deficient. As a result, whole blood serotonin levels are known to be abnormally low in AIDS patients, (44) especially so in those with neuropsychiatric symptoms. Indeed, there is an inverse relationship between serotonin levels in whole blood and AIDS severity. (44) This is not surprising since high doses of serotonin inhibit the multiplication of HIV-1 in T4 lymphocytic cell lines. (45) As Fawkes (46) has pointed out, tryptophan plays a unique role in defense against infection because it is normally relatively scarce. When infection occurs, the body induces tryptophan-catabolizing enzymes in an attempt to starve invading pathogens by increasing tryptophan's scarcity. However, in unresolved infections, like HIV-1, such tryptophan deficiency seems to be linked to neuroendocrine dysregulation, cognitive deficits and immune incompetence. It is not clear when, or if, tryptophan supplementation would be o f benefit to HIV/AIDS patients. However, it has been shown that one of the beneficial effects of zidovudine therapy in patients with HIV infection is the gradual normalization of tryptophan in serum and cerebrospinal fluid. (47) This suggests that tryptophan supplementation is likely to prove beneficial to HIV/AIDS patients.

In addition, it has been demonstrated that the tryptophan derivative niacin, (together with vitamins B1 and C) significantly depresses the progression of HIV-1 infection to AIDS, (48) while serotonin may be able to inhibit HIV-1 in T4 lymphocytic cell lines. (45)

Conclusions

The preceding literature review establishes that HIV-1 is parasitic. Since this virus encodes for glutathione peroxidase, as it replicates it deprives its host of selenium, cysteine, glutamine and tryptophan, eventually causing severe deficiencies of each in HIV-1 seropositive individuals. AIDS is the end product of these declines and the majority of its symptoms are caused by these deficiencies. Selenium and cysteine inadequacies, for example, undermine the immune system in a process that is accelerated by other infectious pathogens. A deficiency of glutamine promotes muscle wasting and digestive malfunction, while a lack of tryptophan and the compounds it biosynthesizes (such as niacin and serotonin) causes dermatitis, diarrhea and various neurologic and psychiatric symptoms including dementia. It is also clear from the literature that supplementation relieves these symptoms and would, therefore, appear to be the most logical treatment for AIDS. The major aim of this treatment would be to return body levels of selenium, cysteine, glutamine and tryptophan to normal. The evidence suggests (7) that this would greatly reduce HIV-1's ability to replicate. Doses, therefore, would vary with the disease stage. It also is probable that niacin and serotonin would prove beneficial.

Acknowledgement

I should like to thank Dr. E.W Taylor for offprints explaining how HIV-1 and certain other viruses encode Sedependent GPx modules.

Information on several chronic disease hypotheses developed by the author is available at http:// www.geocities.com/forsterhd/

Correspondence:

Correspondence and requests for materials should be addressed to H.D. Foster (hfoster@office.geog.uvic.ca).

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