Medical Hypothesis (1996) 46: 388-392

Can we find a solution to the HIV-AIDS controversy?
Is AIDS the consequence of continuous excessive stressing of the body?

A. HASSIG, LIANG WEN-XI AND K. STAMPFLI

The assumption proposed by Gallo in 1984, that the cause of AIDS is infection with HIV viruses was founded on the correlation between the detection of antibodies to these viruses and the onset of AIDS. This view became generally accepted, and today it is still the foundation stone of HIV-virus related measures for the prevention and treatment of AIDS. Duesberg vehemently opposed this opinion. However, although his reasoning was in many respects justified, it was unanimously rejected by AIDS researchers with an interest in virology.[1, 2]

The time for re-evaluation has come, now that methods are available for the direct detection of HIV viruses and for the detection of cellular anti-HIV immune reactions.

In this regard, the work of Bentwich and Jehuda-Cohen of Israel deserves special attention.[3-6] They developed a polyclonal B-cell activation test with which they were able to demonstrate that HIV infections are common among anti-HIV-antibody-negative high-risk individuals. The disease is brought under control by cellular immune reactions and the anti-HIV antibody test remains negative. They also demonstrated that individuals with a positive anti-HIV antibody reaction as a rule showed a pre-existing activation of their immune system at the time of infection. By contrast, the majority of people whose immune system was healthy and normal at the time of infection with HIV showed only a cellular immune reaction by which the HIV viruses had been brought under control and probably partially eliminated from the body.

Strong support for this work came with the reports of Mosmann and Coffman concerning functionally opposing cytokine profiles of CD4 helper lymphocytes.[7] They demonstrated that two groups of cells could be identified among the CD4 helper cells; these they designated Th-1 ancl Th-2 cells. The Th-1 cells secrete preferentially IL-2, IL-12 and IFN-d, which stimulate the cellular immune reactions. The Th-2 cells produce primarily IL-4, IL-6 and IL-10, by which they stimulate the humoral immune reactions. Clerici and Shearer established that displacing the lymphokine profile Th-1 to the Th-2 profile is of crucial importance for the course of HIV infection.[8] Thus, numerous high-risk individuals who are anti-HIV antibody negative show a strong immune reaction of the Th-1 type to HIV antigens. Moreover, these authors have recently reported that the lymphokine profiles Th-l and Th-2 are linked by hormonal equilibrium states between cortisol and dehydroepiandrosterone (DHEA).[9]: cortisol assists the formation of Th-2 cytokines, while DHEA promotes the formation of Th-1 cytokines. Important supporting evidence for the influence of the lymphocytic cytokine profile on the course of HIV infection, which was studied by Clerici and Shearer was brought to light in the investigations of "murine acquired immunodeficiency syndrome" (MAIDS), which is caused by defective mouseleukaemia viruses. IL 4-deficient mice survived infection with this virus, while IL-4 producers succumbed to the disease.[10]

What is the relationship between the lymphocytic cytokine profiles Th-1 and Th-2 and acquired immunodeficiency states in stress reactions?

As we said in our review of AIDS prevention in HIV carriers, an acquired immunodeficiency state is a component of all stress reactions.[11] The concept of stress first described by Selye in 1936 essentially states that the body presents a standard response to the numerous somatic and psychic stresses [12], in which activation of the neuroendocrine stress axis hypothalamus-pituitary-adrenals plays a central role. The increased release of catecholamines and glucocorticoids from the adrenals centralises the metabolism on the supply of rapidly available energy sources, in particular glucose. The glucocorticoids limit the inflammatory reactions and in so doing raise the susceptibility to infection. They reduce the number of lymphocytes and eosinophils and the thymus weight, and are at the centre of suppression of the specific Iymphoplasma-cell immune reactions.

The problem of stress-related irnmunosuppression and its effect on latent viral infections was for more than a decade the area of research of Kiecolt-Glaser and Glaser.[13, 14] In extensive investigations they showed that psychic stress reactions raise the titre of humoral antibodies to viruses such as EBV, CMV and HSV-l, simultaneously attenuating the cellular immune reactions, which are measured in cytotoxic T-cell reactions to these viruses. They explained their findings in terms of the release of latent viruses by the attenuation of cellular defence mechanisms and the secondary stimulation of the formation of humoral antibodies. This interpretation is supported by the observation that the titre of anti-poliomyelitis antibodies is unchanged during stress reactions. Unlike the three herpes viruses mentioned above, poliomyelitis viruses are completely eliminated by the immune reaction after spreading through the body. During their investigations, the authors also observed that the balance between the cyclic nucleotides AMP and GMP, which play a central role in the regulation of lymphocytic metabolic functions, can also be ascribed to the general stress process.[15] The rise in cAMP, which is characteristic for the suppression of all specific cellular immune reactions, is linked to a reduction in cGMP and is concomitant with the decline in cellular immune reactions and the increase in humoral immune reactions.

From what has been said so far it might be supposed that HIV infection can be brought under control by cellular immune reactions in individuals with full immunocompetence, some of the viruses being eliminated and some remaining dormant within the body.

On the immunosuppressant behaviour of high-risk groups: homosexual males, drug addicts of both sexes, haemophiliacs and recipients of blood transfusions

Bentwich and Wainberg [5] have many times since 1985 pointed out that homosexual males not infected with HIV often exhibit marked activation of their immune system. The interferon system [3, 16], the subpopulations of peripheral lymphocytes [3], the elevated cell-bound cytotoxicity [17], and the formation of serum autoantibodies are involved here.[18] Of special note was the finding that the reactivation of an Epstein-Barr viral infection prior to infection with HIV correlated significantly with the appearance of anti-HIV antibodies.[19] The concentration of transforming growth factor in the seminal fluid is relevant in this context. This is an immunosuppressant protein whose function it is to protect the sperm in the vagina from immunological attack by the woman's body. During anal intercourse, it is evidently capable of weakening the immune system of the passive partner.[20]

The immunosuppressant action of opiates has been most widely researched. In studies in mice, chronic administration of morphine causes severe involution of the thymus, characterised by increased apoptosis, primarily of CD4+ / CD8+ thymocytes. The reason for this is probably that morphine increases the formation of corticotropin in the hypothalamus, thereby increasing the formation of ACTH in the pituitary and cortisol in the adrenal cortex.[21, 22] It can thus be assumed that hypercortisolism plays an important role in opiate-induced immunosuppression. To date there have been few investigations of the immunosuppressant effect of cocaine. With regard to its effect on AIDS, let us here refer simply to the animal studies of Lopez and Watson, who showed that in murine AIDS (MAIDS) cocaine dramatically increases the damaging effect of the retroviral infection on the lymphoreticular tissue of the intestinal mucosa.[23]

The question concerning the extent to which immunosuppression in haemophiliacs is correlated with the anti-HIV-antibody status has been researched in detail. The studies of Madhok [24] are of most significance in this regard. The first point to mention regarding this problem is that about half of haemophiliacs produced no anti-HIV antibodies in response to the repeated administration of HIV-contaminated "largepool" coagulation products during the period 1981-1986.[25] To date, no investigations have yet been performed to ascertain whether this patient group has neutralised the HIV viruses by exclusively cellular immune reactions, and then partially eliminated them. However, it is certain that the "large-pool" factor-VIII products in use at that time inhibited the formation of IL-2, thereby weakening the cellular immune reactions.[26] Moreover, at a time when HIV infection was still unknown among haemophiliacs, numerous patients died of acquired immunodeficiency diseases.[27] It must also be considered that, as a consequence of the administration of "large-pool" products manufactured from a large number of pooled plasmapheretic donations from paid donors, the large majority of haemophiliacs used to suffer from chronic hepatitis, which may be regarded as a supplementary immununosuppressant risk. Neither should one underestimate the iron overload as a result of bleeding into the joints and the blood transfusions this necessitated. Haemophiliac immunodeficiency is characterised to particularly good effect by the following two observations. Bedall et al. made the observation that anti-HIV negative haemophiliac adolescents exposed to patients with open tuberculosis developed tbc just as frequently as did children receiving chemotherapy for the treatment of solid tumours.[28] Counter to expectations, in a well-studied group of Dutch haemophiliacs Rosendaal et al. observed a 2.5 times higher mortality rate from cancer.[29] The question currently under debate is whether the genetically engineered factor-VIII products, which evidently do not stress patient's immune system, are suitable substitutes for products manufactured from human plasma.[30]

Pathogenetic mechanisms of acquired immunodeficiency states

The Th-l/Th-2 imbalance of the cytokines of CD4 lymphocytes, which has an immunosuppressant effect, and the displacement of the ratio of the cyclic lymphocytic nucleotides cAMP/cGMP are at least in part attributable to hypercortisolism within the context of stress reactions. This is due to the increased formation of corticotropin in the hypothalamus and the resulting activation of the formation of ACTH in the pituitary and cortisol in the adrenal cortex. In association with sympatheticotonic activation of the autonomic nervous system, which occurs in parallel, this is the standard physiological reaction to all inflamrnatory, toxic, psychic and nutritive stress states. In persistent subclinical stress states there is continuous slight activation of macrophages, with increased formation of monokines and oxygen radicals. This state has a broad tolerance threshold, and can be compensated in the long term. It is manifested as a moderately increased susceptibility to infections and certain degenerative diseases. According to Bentwich and Wainberg, this group includes the many anti-HIV antibody-positive individuals in Africa, Asia and Latin America in whom endemic infections associated with HIV infections favour the humoral immune reaction and weaken the cellular immune reaction.[5, 6] Thus, according to WHO statistics of 1 July 1994, the number of notified AIDS cases in south-east Asia between 1979 and the end of June 1994, which amount to a total of 6739, has so far not risen above the 0.5% threshold of the estimated 2.5 million anti-HIV antibody-positive carriers of the virus.

This group of anti-HIV antibody-positive HIV carriers contrasts with the groups within North America and Europe at high risk of contracting AIDS. In these groups, intensive and continuous stresses play a considerable part in the outbreak of disease. As already mentioned, the persistent activation of macrophages with the release of inflammation mediators and oxygen radicals are prominent in these groups.[31] This leads to increased hypercortisolism which in the lymphoid tissue reduces its most sensitive element, the immature thymocytes, by increased apoptosis, thereby appreciably reducing the number of immunological precursor cells. Gradually the other populations of CD4 helper cells are affected as well, presumably also by HIV viruses, and progressive lyrnphopenia occurs, with a corresponding displacement of the CD4/CD8 ratio. The increasing attenuation of the cellular immune reaction finally leads to activation of the infective agents latent within the body, and thus to the large number of opportunistic inflammatory diseases characteristic of AIDS.

Summary and Conclusions:

If to conclude we now attempt to answer the question of the title "Can we find a solution to the HIV-AIDS controversy?", our present level of knowledge yields the following hypothesis:

HIV viruses are not the only cause of AIDS. Apart from proof that infection with HIV viruses has occurred, a positive result in an anti-HIV antibody test is also an indication of an HIV-independent immunosuppression state. This might explain why the HIV infection was not rendered symptomlessly latent by cellular immune mechanisms.

According to the definition of the Centers of Disease Control (CDC), classical AIDS is the consequence of infection with HIV in association with continuous excessive stress, such as is observed in the known high-risk groups. Also at the centre of the pathogenic process is hypercortisolism-determined damage to the cellular elements of the lymph system, in which insufficiency of thymus is prominent.

For this reason, in our view there are indications for shifting preventive measures more and more from the prophylaxis of infection with HIV viruses to the prophylaxis of AIDS by reducing stress factors. We believe that measures against the excessive formation of O2-radicals as a result of chronic inflammation and nutritive iron overload in the form of antioxidant food supplements will also be important.

Unfortunately, antiviral therapy in HIV-positive individuals and AIDS patients has so far yielded no decisive results in spite of intensive efforts, and it is therefore time that we researchers turn increasingly to reinforcing the defensive capabilities of the host organism. The most important question here is which mechanisms are responsible for the fact that HIV-positive individuals can survive with this retrovirus for many years, or even permanently, without contracting AIDS. *

We are grateful to the Hans Eggenberger Foundation in Zurich, which supported this research. We would like to thank Prof. Dr. med. H. Cottier and E. Lauppi for their valuable assistance.

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English translation of an article which was first published in the Swiss Journal of Holistic Medicine (Schweizerische Zeitschrift fur Ganzheits Medizin) Oct. 1994