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

Townsend Letter for Doctors and Patients, April, 2002 by Harold D. Foster

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.