"Co-factors" Cause AIDS
This article was written in June 2000
and posted during the Internet Discussion
of the South African Presidential AIDS Advisory Panel
Since it has never been scientifically proven that HIV destroys the immune system and causes AIDS (1), investigators who enthusiastically defend HIV as the cause of the syndrome have proposed a vast variety of agents as helpers, or ‘cofactors", of HIV in the genesis of AIDS (2,3). However, these "cofactors" are by themselves causal agents of immunodeficiency and can generate AIDS with or without the presence of a positive result on the antibody tests for HIV (4,5). I prefer to call the so-called "cofactors" immunological stressor agents that can have chemical, physical, biological, mental, and nutritional origin (6,7).
The following are some of the agents that have been proposed as "cofactors" for HIV: alcohol, cocaine, heroine, morphine, marihuana, cigarette smoking, amphetamines, volatile inhalants like "poppers", environmental chemical pollutants, allergens, CMV, herpes virus type 1, 2, & 6, herpes zoster, EBV, adenovirus, retroviruses other than HIV, hepatitis A, B, & C viruses, papovavirus, mycoplasmas and other superantigens, tuberculosis, leprosy, malaria, trypanosomiasis, filariasis, other tropical diseases, sexually transmitted diseases, semen, blood, factor VIII, anxiety, depression, lack of sleep and rest, exhaustible exercise, unsanitary conditions, poverty, malnutrition, and several vitamin deficiencies (2,3,8-11).
Let us see briefly how multiple, repeated and chronic exposure to immunological stressor agents¾ "cofactors" ¾ can degenerate the immune system and cause AIDS:
1. Role of Chemical Stressors in Immunodeficiency
Practically every single medicament from the following groups have been found to have immunotoxic properties: antibiotics; antifungal, antiviral, and antiparasitic agents; tranquilizers, antiepileptics, antiparkinson, and anesthetics; antihypertensive, anti- anginal, and antiarrhythmic drugs; gastrointestinal medications; antidiabetics, antithyroid drugs, and sex hormones including oral contraceptives; antiallergics; bronchodilating agents; anticoagulants, drugs acting on fibrinolysis, blood expanders, clotting factors, and inhibitors of platelet aggregation; non-steroidal anti-inflammatory drugs, corticosteroids, antirheumatismal, and anti gout drugs; and immunodepressive and immunomodulating drugs such as antitumoral drugs and medications to avoid graft rejection (12-14). The immunotoxicity of AZT has been solidly documented (15-18).
Industrial, chemical, and environmental pollutants are another important source of various abnormalities upon lymphocyte activation, proliferation and differentiation, cytokine production, cytotoxic effect, antibody production, phagocytosis, natural killer cell activity, complement, etc., (19,20). Additionally, immunotoxicity has been found in practically every single chemical that has been tested from the following groups: heavy metals, pesticides, aliphatic and aromatic hydrocarbons and derivatives, alcohols, phenols, and derivatives, airborne pollutants including diesel engine emissions, nitrogen dioxide, ozone, sulfuric acid and food additives and preservatives (13,14,21).
The adverse effects of alcohol and other drugs on the immune system have been documented since the beginning of the last century (22). There is a growing body of human and animal evidence concerning the immunotoxicity of tobacco smoke, alcohol, marijuana, cocaine, heroine, alkyl nitrites, met amphetamines, qualones and other street drugs (23-30). These facts in part form the scientific base for the "drug-AIDS hypothesis" (15,16,31,32).
Chemical stressors can act as free radicals or stimulate the production of them (33-35).
2. Role of Physical Stressors in Immunodeficiency
There is evidence that a variety of physical stressors lead to immunodeficiency. Lymphocytes are much more radiosensitive than macrophages and plasma cells, and alterations of the immune cells are in a dose-dependent fashion. Radiation victims frequently succumb to infection (36,37).
Ultraviolet B radiation (UV) has often been implicated in local and systemic immunosuppression (38). UV exposure decreases the counts of total and helper T lymphocytes with inversion of T4/T8 ratio (33). It also decreases plasma carotenoids, potent antioxidants (39).
Exposures to other non ionizing radiations such as electromagnetic fields, visible light, infrared, radio frequencies and microwaves, lasers, and very low and extremely low radiation frequencies have been shown to increase the risk of degenerative diseases and certain cancers (40-44).
Vibration, heat, and high altitude stressors are also connected to degenerative diseases in which the immune system is known to play protective roles (45-46).
Free radicals have been clearly connected with physical stressors and cell injury (33,35,47,48).
3. Role of Biological Stressors in Immunodeficiency
The immunogenic properties of the components of human semen are known to induce chronic stimulation of the immune system with subsequent immunosuppression (49,50). Lymphocytotoxic autoimmunity is proposed as a mechanism for this phenomenon (51). Passive anal intercourse is recognized as a strong risk factor for AIDS (52-55), even for HIV-negative individuals (47).
Blood and its components are known to be immunosuppresive (56). It has been suggested many times that the immunological abnormalities occurring in hemophiliacs are secondary to the immunogenic properties of foreign proteins in the whole blood, in commercial clotting factor VIII, or to factor VIII itself (56-61). The hemophilia immunologic dysfunctions are obviously proportional to the lifetime dose of therapy received (61). Immunodeficiency has been described multiple times in HIV-negative hemophiliacs (62,63). On the other hand, no immunosuppression has been observed in hemophiliacs treated with available purer factor VIII preparations (64). These facts in part form the base for the "foreign-protein-hemophilia AIDS hypothesis" (58).
A necessary prerequisite for any infectious agent developing potential pathogenic properties is host immunodeficiency (65). On the other hand, and as a consequence of the host-infectious-agent relationships, immunosuppression, especially of the cell-mediated immunity, occurs during all infectious diseases (66). This is particularly valid in intracellular infections¾ gonorrhea, listeriosis, legionellosis, brucellosis, chlamydial infections, mycoplasma infections, rickettsial infections, salmonellosis, tularemia, yersinia infections¾ and with all viral diseases (66,67). Immunodeficiency is also the rule during infections with poly-immunogenic organisms leading to granuloma formation, such as spirochetes (syphilis, bejel, yaws, pinta); mycobacteries (tuberculosis, leprosy); fungi (dermatomycosis, sporotrichosis, chromomycosis, histoplasmosis, blastomycosis, coccidioidomycosis, paracoccidioidomycosis, cryptococosis, pneumocystosis, aspergillosis, mucormycosis, candidiasis); protozoa (toxoplasmosis, malaria, leishmaniasis, trypanosomiasis, amoebiasis, giardiasis); helminths (intestinal helminthes, cysticercosis, hydatidosis, filariasis, schistosomiasis, fluke infestations, toxocariasis) (66,68-71).
The role of parasites and infections as a cause of immunosuppression in the underdeveloped world has been addressed many times (8,10,11,72).
Reactive free radicals have been implicated in the generation of immunodeficiency during the course of infectious diseases (73-75).
4. Role of Mental Stressors in Immunodeficiency
Since the times of Galen (200 AD) it has been of public knowledge that the mind can influence the body (76), particularly in disorders related to immunity (77). Different immunological abnormalities have been found in people under psychosocial stress (78). For example, anxiety and depression decrease lymphocyte counts and functions (79). Academic stress lowers natural killer cell activity, blastogenesis, and interferon production (80). Bereavement decreases lymphocyte proliferative response to mitogen and lowers natural killer cell activity (81). DNA repair capability in lymphocytes is highly impaired by mental distress (82).
Only in the last three decades have the mechanisms that allow mental stressors to cause immunodeficiency been clarified (77,83-86).
Lymphocytes are known to produce various hormones and neurotransmitters, originally believed to be produced only by endocrine glands and neurons (87,88). At the same time, lymphocytes have receptors for all types of hormones and neurotransmitters, including endorphins and encephalins (87). Neurons and cells from endocrine glands have receptors for lymphokines (87). Therefore, brain, mind, endocrine glands, and lymphoid tissues are biochemically interconnected (89), structuring a critical part of our defense activities. Furthermore, all types of stressors (chemical, physical, etc.) share pathways during any stress response to them (90).
The issue of mental stress as an immunodepressive agent has been addressed many times in relation to the onset, course, and prognosis of AIDS (78,91,92).
5. Role of Nutritional Stressors in Immunodeficiency
The effects of malnutrition on lymphoid organs were first described during the middle of the 19th century (93). Lymphoid tissues are particularly vulnerable to the damaging effects of malnutrition, and lymphoid atrophy is a prominent feature in nutritional deprivation (94). Cell division is a very singular characteristic of the functioning of immunocompetent cells. All types of immune cells and their products, such as interleukins, interferons, and complement, are known to depend on metabolic pathways that employ various nutrients as critical co-factors for their actions and activities (94). Most of the host defense mechanisms are altered in protein-energy malnutrition [PEM], as well as during deficiencies of trace elements and vitamins (95).
Patients with PEM have impaired delayed cutaneous hypersensitivity, poor lymphocyte proliferation response to mitogens, lower synthesis of lymphocyte DNA, reduced number of rosetting T lymphocytes, impaired maturation of lymphocytes seen through an increased deoxynucleotidyl transferasa activity, decreased serum thymic factor, fewer CD4+ cells, decreased CD4+/CD8+ ratio, impaired production of interferon gamma and interleukin 2, altered complement activity (especially reduction of C3, C5, factor B and total hemolytic activity), poor secondary antibody response to certain antigens, reduced antibody affinity, impaired secretory immunoglobulin A response, decreased antibody affinity, and phagocyte dysfunction (94).
Human malnutrition is usually a composite syndrome of multiple nutrient deficiencies. However, isolated micronutrient deficiencies do happen. Vitamin A deficiency results in reduction in the weight of the thymus, decreased lymphocyte proliferation, impaired natural killer cell and macrophage activities, and increased bacterial adherence to epithelial cells (96). Vitamin B6 deficiency produces failure of several components of both cell-mediated and humoral immune responses (94). Vitamin C deficiency impairs phagocytosis (97) and cell-mediated immune reactions (102). Vitamin E deficiency also alters immune responsiveness (94). Zinc deficiency generates lymphoid atrophy, reduces lymphocyte responses and skin delayed hypersensitivity (94). Copper and selenium deficiencies impair T and B lymphocyte functions (94). Dietary deficiencies of selected amino acids such as glutamine and arginine also alter immunity (94).
Intrauterine malnutrition causes prolonged, even permanent, depression of immunity in offspring (98,99).
Considerable data implicate excess lipid intake in the impairment of immune responses (100). The potential for free radical damage is dependent in large part on the level of potentially oxidizable fatty acids, mainly polyunsaturated fatty acids (PUFAs) in the diet (33). High levels of dietary PUFAs have been shown to be immunodepressive. Dietary fats may undergo free radical-mediated oxidation prior to ingestion, as can occur when foods are fried (33). Animals fed oxidized lipids show marked atrophy of the thymus and T lymphocyte dysfunctions (100,101).
At the molecular level, the damage to immunocompetent cells by several nutritional deficiencies (Vitamin A, Vitamin C, Vitamin E, zinc, copper, zelenium deficiencies) is caused by increased free radicals through oxidative stress (94,102).
As Jain and Chandra (9) have found, "...there is an uncanny similarity between the immunological findings in nutritional deficiencies and those seen in AIDS". The role of nutritional stressors in AIDS has been addressed many times (103,104).
6. Role of Free Radicals in Immunodeficiency
Free radical reactions of special significance to immunological phenomena are, for example, many oxidizing agents that can abstract a hydrogen atom from thiol groups to form thiyl radicals. Thiol groups are important for enzyme activities, receptor functions, disulphite links in immunoglobulins, and T cell activation and proliferation (105). The super oxide anion radical can react with nitric oxide resulting in loss of endothelium-derived relaxing factor activity (106), which is important in the inflammation/disinflammation process. Methionine oxidation can cause protein damage with subsequent changes in immunogenicity (107). Proteolysis can be increased by free radical damage (108). The per oxidation of lipids by reactive free radicals produce many biological modulators as, for example, the 4-hydroxy-alkelans which produces strong chemotactic activity for phagocytes (109), alters the adenyl cyclasa system, increases capillary permeability, and alters lymphocyte activation (110). Lipid hydroperoxides, also from per oxidation of lipids, alter lymphocyte activation (110). Conditions favoring lipid per oxidation may result in chemo taxis of leukocytes, protein modification, immune complex injury, and cell death (105).
Free radicals are produced over the regular immune system network. Despite the beneficial effects of the inflammation responses, they can also aggravate existing tissue damage by releasing free radicals. When uncontrolled, initiated by an abnormal stimulus, or occurring for prolonged periods of time, inflammation may become the disease process (111). It is critical for optimal immune responses that there be a balance between free radical generation and antioxidant protection (33). During phagocytosis by polymorphonuclear leukocytes for example, super oxide anion radicals are released (112). These oxygen free radicals can oxidize thiol groups to thiol radicals, and can stimulate lipid per oxidation with the formation of H2O2, which is very significant in the mechanisms of cell injury (105). Oxygen free radicals produced during phagocytosis of immune complexes are associated with injury due to immune complexes (113).
It has been proposed several times that free radicals and specifically oxidizing species play important roles in the pathogenesis of AIDS (55,114-121).
7. Conclusions
I propose that at a physiological level, AIDS can be explained as a progressive degenerative alteration of different immune cells and immune metabolic reactions, secondary to multiple, repeated, and chronic exposures to immunological stressors. This degeneration can be caused by an immunotoxic effect of stressors on immunocompetent cells. Also, it can be the result of over stimulation/activation of the immune cells through an immunogenic effect. Many chemical and biological stressors can have an immunogenic effect on the immune cells and functions. Additionally, physical, mental, nutritional, and, again, chemical stressors can have an immunotoxic effect on the same cells and activities (4,5).
At a molecular level, AIDS is the result of alterations of immunocompetent cells and immune metabolic reactions due to an excess of free radicals, especially oxidizing agents. Since 1988 Eleni Papadopulos-Eleopulos has been elegantly describing the role of oxidizing agents in the pathogenesis of AIDS (119).
AIDS is neither an infectious disease nor is sexually transmitted. It is a toxic/nutritional syndrome caused by the alarming worldwide increment in immunological stressor agents.
8. Trial Proposal
I propose the following experiments to find out the real role of immunological stressors¾ co-factors¾ in the causation of AIDS:
Have three groups of people: a) symptomatic AIDS patients; b) HIV-positive asymptomatic individuals; and c) very healthy HIV-negative individuals.
The AIDS patients as well as the HIV-positive asymptomatic groups should include individuals from all the groups at risk for AIDS; drug addicted and non-drug addicted gay males, IV and non-IV drug addicted individuals, prostitutes, hemophiliacs, blacks and Hispanics in the USA, Africans and Asians, children from developed and underdeveloped countries, AIDS-phobic people, and an occupational group. The normal individuals to be used as controls should match as closely as possible the individuals in the other two groups.
Retrospective trial¾ before starting any treatment the three groups should be checked for:
· Exposure to immunological stressors of chemical, physical, biological, mental, and nutritional origin. A questionnaire should be used to determine retrospectively past exposures to chemical, physical, biological, mental, and nutritional immunological stressors.
· Levels of oxidizing agents. Test all groups for the presence and levels of surrogate markers of oxidation.
· "HIV status." Test all individuals in each of the three groups with the ELISA, Western blot, and PCR tests.
· Immune system response capabilities. In addition to counting all the T and B cell subsets, it is necessary to evaluate the functioning status of lymphocytes, as well as all other immunocompetent cells, by tests such as lymphoblastotransformation, inhibition of migration, lymphocyte activation, etc. Test the levels of all components of the complement system. Test electrophoresis of proteins, immunoelectrophoresis, levels of serum immunoglobulins G, A, M, D, and E. Test for the presence of all types of autoantibodies, circulatory immune complexes, and skin test reactions. Test for Beta 2 microglobulin.
· Physiological status of all other systems. Run complete chemical, hematological, urine and stool profiles. Also test the status of the endocrine glands, liver, and kidneys. Determine levels of micronutrients such as B-complex vitamins, Vitamin C, betacarothene, vitamin E, selenium, zinc, magnesium, etc. Test Beta 2 microglobulin.
Prospective trial¾ follow the three groups for several years with periodic clinical and laboratory evaluation.
REFERENCES
Roberto A. Giraldo
www.RobertoGiraldo.com