Thoughts on the pathogenesis and prevention of AIDS

By A. Hassig, Liang Wen-Xi and K. Stampfli
English translation of an article which is published in the Swiss Journal of Holistic Medicine (Schweizerische Zeitschrift fur Ganzheits Medizin) July 1995.

Summary

In the last few years, AIDS research has concentrated on the opposite behaviour of humoral and cellular immune reactions. In 1986, Mosmann and Coffman demonstrated that two cell groups can be differentiated amongst the CD-4 helper cells, which they referred to as Th-1 and Th-2 cells. The Th-1 cells preferably secrete IL-2, IL-12, and IFN-y , which stimulate the cellular immune reactions. The Th-2 cells produce primarily IL-4, IL-6 and IL-10, and thus stimulate the humoral immune reactions. After Clerici and Shearer were able to establish that the Th-2 cytokine profile favoured the development of AIDS in HIV-infected patients, whilst the Th-1 cytokine profile inhibited the development of AIDS, a large share of the present research work done into AIDS concentrated on the cytokine profiles of the cells of the immunological system.

The most signifcant progress in this field was achieved by the study group of Daynes, which was able to demonstrate that the regulation of cytokine production by activated lymphocytes take place in the periphery. Mitogenic or antigen-stimulated lymphocytes in lymphoid organs in the region of the mucous membranes produce preferably IL-4. Lymphocytes from internal organs primarily produce IL-2 and IFN-y. The decisive factor for the type of peripheral regulation of the lymphocyte cytokine production is the production of steroid hormones which are produced locally from inactive preliminary stages. In this process, Dehydroepiandrosterone (DHEA) produced in the cortex of the suprarenal gland plays an important role as an antagonist to cortisol. DREA produced in the cortex of the suprarenal is sulphated (DHEAS) and is inactive in this form. The different concentration of steroid sulphatase in different tissues plays the main role in the transformation of the prehormone DHEAS into active DHEA in the production of Th-l, respectively Th-2 lymphocytes. It was found that the cortisol to DHEA ratio for cellular and humoral immune reactions is balanced for the Th-1 cytokine profile, whilst the Th-2 profile of the lymphocytic cytokine has an excess of cortisol. Here, a stress-induced excess of cortisol is of major interest in the Th-2 profile related development of AIDS. Hence, the role of HIV infections as a sole decisive reason for the outbreak of AIDS is relativised which is underscored by the comparison of AIDS with other aquired immune deficiency conditions, such as in children suffering from kwashiorkor syndrome and maramus, and those patients suffering from a sepsis syndrome after polytraumata, burns, and severe surgical interventions.

The most valuable parameter of increasing hypercortisolism in the transformation from the symptom-free carrier state of opportunists into AIDS related complex (ARC) and to full blown AIDS is the decrease in CD-4 lymphocytes aside of an almost stable number of CD-8 lymphocytes. These findings were established originally by the study group around Fauci, who no longer mentioned his previous works after the decision was taken by the experts of the Centres of Disease Control (CDC) that HIV infections were the sole reason for AIDS. Fauci's works on the influence of cortisone on the CD-4 to CD-8 ratio in the lymphozytes also provided a plausible explanation for long-time survival of HIV-infected patiens, who have overcome the HIV infection not exclusively by cellular immune reactions, as is the case in immunologically healthy persons. In addition, a humoral immune response with the production of anti-HIV anti-bodies occurred, which remained in the neuro-endocrine Th-1 situation and which did not perform the transformation into the Th-2 situation along with hypercortisolism required for the outbreak of AIDS, thus sparing the patients this disease.

Introduction

When looking at the pathogenesis of AIDS without prejudice, an acquired deficiency of the cellular immune reactions is found which causes an increasing release of opportunistic infective agents which are kept at bay by a healthy organism without clinical manifestatioens (1).

In investigating the mechanisms of this deficiency of the cellular immune reactions, the works of Glaser and Kiecolt-Glaser (2) are encountered. In extensive studies they have shown that psychological stress reactions increase the titre of humoral antibodies against viruses, such as EVB, CMV, and HSV-1; at the same time, however, they weaken the cellular immune reactions - measured on the cytotoxic T-cell reactions against these viruses. They explained their findings by the release of latent viruses on account of the deficiency of the cellular defence mechanism and the secondary stimulation of the production of humoral antibodies. This explanatory approach is supported by the observation that the titre of antipoliomyelitis antibodies does not change in the event of stress reactions. After spreading in the body, poliomyelitis viruses are completely eliminated by the immune reaction which does not apply for the three herpes viruses mentioned.

The opposite behaviour of the humoral and cellular immune reactions observed in these works were substantiated considerably by the reports of Mosmann and Coffman on the functionally opposite cytokine profile of the CD-4-helper lymphocytes.(3) They demonstrated that two cell groups, which they termed Th-1 and Th-2 cells, can be different in the CD-4-helper cells. Th-1 cells preferably secrete IL-2, IL-12 and IFN-y , which stimulate the cellular immune reactions. Th-2 cells predominantly produce IL-4, IL-6 and IL-10, and thus stimulate the humoral immune reactions. These findings met with great interest when Clerici and Shearer were able to show that the Th-2 cytokine profile in HIV infected virus carriers favoured the development of AIDS, whilst the Th-1 cytokine profile inhibits the development of AIDS.(4) They demonstrated that numerous anti-HIV negative high-risk persons had a strong immune reaction of the Th-1 type against HIV antigens, which means that the infection in persons infected by HI viruses does not always cause a responsive reaction by the production of anti-HIV antibodies, and thus by a positive anti-HIV test. The theory of an HIV infection being influenced by the lymphocytic cytokine profile propagated by Clerici and Shearer was supported by the studies on the "murine acquired immunodeficiency syndrome " (MAIDS), which is caused by murine leukaemia viruses. IL-4 deficient mice survived the infection with this virus, whilst IL-4 producing mice died from the disease (5). Contradictory results were observed with respect to Th-1 / Th-2 profiles in anti-HIV positive persons and AIDS patients. Particularly Romagnani and Fauci expressed their doubts about the clinical significance of the findings obtained by Clerici and Shearer.(6,7) No uniform opinion could be stated during the first international symposium on HIV and cytokines, which took place in Reims from 15th to 17th March 1995.(8)

Endocrine regulation of the Th-1 / Th 2 balance of the cytokine production in CD-4 lymphocytes

This controversy can be solved, however, if the Th-1/Th2 balance in the cytokine production of the CD-4 lymphozytes is related to the dynamic neuro-endokrine conditions of the immunological system in stress reactions.

It has to be noted, however, that it was known that glucocorticoids drastically inhibit the production of IL-2 and IFN-y before the Th-1 and Th-2 cytokine profiles of CD-4 lymphocytes was described.(9) The significant step towards the clarification of the mechanisms behind the production of these lymphozyte cytokine profiles was made by the study group around Daynes.(10,11) The group revealed first of all that the regulation of the cytokine production of activated lymphocytes takes place in the periphery. Mitogen or antigen stimulated lymphocytes from lymphoid organs in the region of the mucous membranes preferably produce IL-4. Lymphocytes from internal organs preferably produce IL-2. The decisive factor for the type of peripheral regulation of the lymphozyte cytokine production is the production of steroid hormones which are produced locally from inactive precursors. In this process, the dehydroepiandrosterone (DHEA) produced in the cortex of the suprarenal gland plays an important role as an antagonist to the cortisol. DHEA is the adrenocortical hormone in the blood which is contained in the highest concentration of all steroid hormones. It is sulphated (DHEAS), and inactive in this form. By means of steroid sulphatase, DHEA is desulphated in the periphery, and thus transformed into the active form. In the lymphocytes the active DHEA causes an increased production of IL-2 and IFN-y , 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-l, respectively Th-2 lymphocytes. The sulphatase activated by macrophages is inhibited by IFN-a , IFN-b, and TNF-a , but not by IL-1, IL-6, and IFN-y. In the lymphatic tissue, the macrophages are the only cells which have a quantity of DHEAS sulphatase worth mentioning. Moreover, the high concentration of circulating DHEAS is used as a reservoir for the production of androgenic and secondary also of oestrogenous hormones.

Stress-related immunosuppression

How can these new findings be related to the complex of problems in stress-related immunosuppression? As we demonstrated in our previous studies already, an acquired immunodeficiency is a factor of every stress reaction. The essence of the stress concept presented by Selye in 1936 implies that the organism responds to the versatility of somatic and psychic load in a uniform way. In this respect, the activation of the neuro-endocrine stress axis between the hypothalamus, pituitary gland and the suprarenal gland plays a central role. The increased release of catecholamines and glucocorticoids by the suprarenal gland causes a centralisation of the metabolism for the provision of rapidly available energy sources, primarily glucose, required for increased muscular performance in a fight- or flight situation. The physiological function of the glucocorticoids is to limit the life-threatening acute phase reaction by endogenic inflammatory mediators. In this process, a higher concentration of cortisol causes a substantial suppression of the T-cell related cellular immune reactions, and thus an increased susceptibility of infections by nosocomial pathogens and opportunists.(9)

From this point of view, we consider it imperative that the neuroendocrine mechanisms of stress-induced immunosuppression are emphasized in the research of AIDS pathogenesis. It should be noted that the transformation of the lymphocytic cytokine profile from Th-1 and Th-2 as well as the depletion of CD-4 T-cells are a general occurrence in numerous chronic infections so that the HI-viruses have to be viewed alongside the multitude of causative agents of chronic inflammatory diseases.(12) Hence, the bonding of gp 120 of the HI viruses to the surface structure of the CD-4 cells and subsequent apoptosis of these cells by no means can be considered the sole reason for the depletion of CD-4 T-cells in AIDS. Typical examples for the Th-1 and Th-2 transformation are schistosomiasis and syphilis. The depletion of CD-4 cells, and thus the accompanying change in CD-4 to CD-8 ratio, is also found in tuberculosis patients and clinical pictures similar to AIDS in anti-HIV negative patients.(12)

As can be seen from the elaborations above, the Th-1/Th-2 balance of the lymphocytes is determined decisively by the local balance of the steroid hormones cortisol and DHEA at the location of their activation. Here DHEA is the local antagonist to the systemic cortisol.

As it is considered safe today that a persisting hypercortisolism plays an important part in the pathogenesis of AIDS, note should be taken that in the process the most cortisol sensitive elements of the lymphoid tissue, i.e. immature thymocytes, are reduced by increased apoptosis, whereby the number of immunological precursor cells decreases rapidly. In this respect, it remains to be clarified whether T-cells are eliminated to a higher degree by repeated stimulation caused by increased apoptosis in the presence of an excess of cortisol relative to DHEA in the periphery.

The fact that hypercortisolism has a decisive significance in the pathogenesis of AIDS is substantiated by the well-known fact that pneumocystis carinii pneumonia occurs in case of hypercortisolism only.(14) The same applies for the inflammation of the mucous membranes caused by candida infections.

Comparison of AIDS to other acquired immunodeficiency conditions

Basing on the statements made above, AIDS is caused primarily by the fact that the macrophage activation characteristic for acute phase reactions is not returned to the homeostatic standard in time, but rather leads to an advanced "whole-body inflammation" on account of persisting hyercortisolism. The increasing deficiency of the T-cell related cellular immune reactions is characteristic for this action.

The same process takes place in children undernourished in proteins suffering from the kwashiorkor syndrome and marasmus. Most suitably, Beisel referred to this group of diseases as "nutritionally acquired immune deficiency syndromes" (NAIDS), and pointed out that every day about 40,000 children below the age of 5 all over the world die of this disease.(15) The children suffer from an atrophy of the thymus accompanied by a severe deficit in T-lymphocytes in the lymphatic nodes and the spleen. Like in the case of AIDS, they die of infections caused by intra-cellular opportunists, such as Pneumocystis carinii, Herpes simplex or anergic miliary tuberculosis (16).

In addition, it has to kept in mind that the sepsis syndrome frequently observed in the event of polytraumata, burns, and severe surgical interventions is also caused by an excessive and persisting inflammation of the entire organism, and thus may be considered as acute AIDS. The central role of an excessive macrophage activation is substantiated by the fact that like in the case of AIDS the concentration of neopterin released by the macrophages is closely linked to the survival or death of the patient.(17,18)

Possibilities of transforming a Th-2 profile into a Th-1 profile in the CD-4 lymphozytes

As it may be considered certain now that the Th-2 cytokine profile of the CD-4 lymphocytes occurs in case of an excess in cortisol along with a deficiency in DHEA, whilst the quantity ratio between glucocorticoids and DHEA in the Th-1 profile is normal, the question arises how a Th-2 profile can be transfomed into a Th-1 profile endocrinologically. In a vast majority of cases hypercortisolism is the sequel of a stress reaction accompanied by an increased production of the corticotropin releasing hormone (CRH) in the hypothalamus which increases the production of ylucocorticoids, particularly cortisol, in the cortex of the suprarenal gland due to increased production of ACTH in the pituitary gland.

In case of psychological stress reactions, the activation of CRH takes place in the cerebrum. In the development of AIDS, the iatrogenic frightening of the HI virus carriers, who are told that any infection with this virus will lead to AIDS sooner or later and thus to death, is a severe psychological stress. Recently, the study of long-term survivors has shown that HIV infections with the development of anti-HIV anti-bodies by no means always leads to the development of AIDS.

The immunosuppressive action of opiates is described best for the toxic stress reactions. In animal experiments on mice, a chronic administraion of morphine caused a severe thymus involution characterised by an increased apoptosis, primarily of immature CD4+-CD8+ thymocytes. This action is based on the fact that morphine increases the production of CRH in the hypothalamus and thus activates the production of ACTH in the pituary gland and of cortisol in the cortex of the suprarenal gland.(19,20)

The most important reason for persisting stress reactions is the dysregulation of the macrophage activation accompanied by the deficit of IL-2 and IFN-y releasing O2 radicals and monokins as inflammation mediators . IL-1, TFR-a , and IL-6 are strong activators of the CRH production in the hypothalamus, causing an increase in the production of cortisol in the cortex of the suprarenal gland via the ACTH production in the pituitary gland.

The characteristic feature for the transformation from symptom-free carrier state of opportunists into AIDS-related complex (ARC) and into full blown AIDS is the rising decrease of CD-4 lymphocytes along with an almost stable number of CD-8 lymphocytes. The decrease of CD-4 cells is primarily an expression of hypercortisolism. In this respect it is noteworthy that Fauci and his study group demonstrated in the 70s that hypercortisolism is the main reason for the selective decrease in CD-4 cells, whereby they are primarily sequestered in the bone marrow.(21,22,23) Fauci's group used pharmacological doses of cortisol administered in vivo. Antonazzi (24) and Calvano (25) pointed out that the same CD-4 cell decrease can be observed in patients suffering from burn. In this context, Calvano demonstrated that it is not sufficient to determine the total cortisol in the serum. The decisive factor for the cortisol action is the concentration of big-active cortisol which increases dramatically in case of a decrease in cortisol-binding plasma proteins (transcortin, albumin). In retrospect, we consider it to be inexplicable that Fauci never again mentioned his earlier studies on the effect of cortisol on the CD-4 to CD-8 ratio in lymphocytes after the decision was taken by the experts of the Centres of Disease Control (CDC) that HI-viruses are the decisive reason for AIDS and the decrease of CD-4 lymphocytes observed.

The earlier studies of Fauci provide a plausible explanation for the long time survival of HIV-infected patients, who have overcome the HI infection not exclusively by cellular immune reactions, as is the case in immunologically healthy persons. In addition, a humoral immune response with the production of anti-HIV anti-bodies occurred, which remained in the neuro-endocrine Th-1 situation, and which did not perform the transformation into the Th-2 situation along with hypercortisolism required for the out-break of AIDS, thus sparing the patients this disease.

How can the vicious-circle of dysfunctioning macrophage activation be interrupted?

The answer to this question lies in the inhibition of the pro-inflammatory macrophage activation. In this respect, the correction of an oxidative stress situation is crucial. For this reason, it seems imperative to remove such a deficiency. We have dealt with this problem in a prelimanary study on AIDS preventions for HI virus carriers.(26) Here, we want to mention only the possibility of cortisone inhibition by means of glycosaminoglycans (GAGs), such as chondroitinsulphate which play an important role in the treatment of arthrosis and osteoporosis.(27)

In conclusion, we are of the same opinion as Root-Bernstein that the decision taken at the time that HI viruses are the sole decisive causative factor for AIDS considering the other risk factors as co-factors was rash and incorrect in retrospect.(28) According to our opinion, it is the sum of the risk factors which causes a severe stress-induced deficiency of the T-cell related immune reactions which in turn lead to the release of a large number of opportunists.

In view of the failure in antiviral prevention and treatment of AIDS we consider it imperative that now intensive studies should be devoted to the support of the defensive powers of the host organisms, i.e. to the immune restitution of stress-induced immunosuppressions. *

We wish to thank Hans- Eggenberger-Stiftung of Zurich, Switzerland, for supporting this study.

Addendum

The hypothesis forwarded in the above text, i.e., the suppression of cellular immune reactions concomitant with a predominance of a Th-2 profile of CD4 lymphocytes may be a prerequisite for the development of AIDS in HIV carriers, finds support in the following two recent reports: a) Carbonari and coworkers (1) showed in 1994 that most apoptotic lymphozytes in AIDS-patients correspond to CD8 T-cells and CD19+ B-cells. The authors conclude from these findings that the phenomenon of apoptosis in vitro of lymphocytes obtained from individuals with AIDS is not correlated with the numerial diminution of CD4+ cells in these patients. b) Finkel (2) has recently demonstrated that the enhanced apoptosis of lymphocytes from anti-HIV positive individuals does not preferentially concern the virus-containing cells, most of the latter being spared from this type of cell death. In their comment to these findings, Pantaleo and Fauci (3) offer no explanation for this phenomenon. In our judgement, the above observations are consistant with the notion that the progressive disappearance of CD4 cells in HIV-carriers in the process of developing AIDS may be a manifestation of a persistent acute phase reaction. We therefore postulate that any attempt to prevent the outbreak of AIDS in HIV-carriers should primarily comprise the avoidance of stress-induced immune suppression.

1. M. Carbonari et al: Detection and Characterization of Apoptotic Peripheral Blood Lymphocytes in Human Immunodeficiency Infection and Cancer Chemotherapy by a Novel Flow Immunocytometric Method. Blood 83, 1268 (1994)

2. T.H. Finkel: Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV-and SIV-infected lymphnodes. Nature Medicine 1, 129 (1995)

3. G. Pantaleo, A.S. Fauci: Apoptosis in HIV-infection. Nature Medicine 1, 118 (1995)  

References