Toughts on the pathogenesis and prevention of AIDS
A. Hassig, Liang Wen-Xi and K. Stampfli
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)
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