Continuum vol.3 no.5
Reappraisal of the depletion of circulating CD4+ lymphocytes
in HIV-carriers in transition to AIDS
Prof. Alfred Hässig, Prof. Liang Wen-Xi and Dr. Kurt Stampfli
A characteristic for the transition from asymptomatic HIV infection to
AIDS-related complex and to full-blown AIDS is the continual reduction
in the number of CD4-lymphocytes in the blood while the CD8-lymphocyte
count remains practically constant. According to current wisdom, this is
because of the increasing destruction of CD4-cells by HIV.
Last year however, Carbonari et al showed that apoptotic (apoptosis
= programmed cell death) lymphocytes in AIDS patients consist for the most
part of CD8 T-cells and CD19
B-cells.(1) They concluded from this that the phenomenon of in-vitro apoptosis
might not be related to the depletion of CD4 T-cells in AIDS. Finkel et
al recently showed that apoptosis occurs predominantly in bystander
cells and not in productively infected cells of HIV- and SIV-infected lymph
nodes.(2) In their commentary, Pantaleo and Fauci did not wish to give
any conclusive answer to this.(3)
In order to clarify the question of the cause of the increasing depletion
of CD4-cells in the transition from healthy ‘HIV’-carrier to AIDS patient
it seems to us to be useful to make a critical review of the studies of
this phenomenon which appeared before the first description of AIDS in
In the mid-’70s Fauci and his working group showed that after the administration
of cortisol (a hormone produced by the adrenal glands in response to stress)
the body appeared to respond with a selective reduction in the number of
CD4-cells. This was found to be because most of this sub-group of white
blood cells migrated from the blood circulating in the blood vessels into
other areas of the body outside the vascular system.(4,5,6) After the withdrawal
of cortisol, the CD4-cells return to the circulating blood and CD4/CD8
ratio returns to normal.
With regard to where the CD4-cells migrate under the influence of cortisol,
it has been shown in animal experiments that they are sequestered mainly
into the bone marrow.(4,7,8) Following these studies Antonacci and Calvano,
from the working group of Shires, showed that a similar depletion of CD4-cells
is also seen in burn patients.(9) Calvano also demonstrated that in cases
of burns the body’s own bioactive cortisol level rises sharply.(10) These
investigators concluded from their findings that the sequestration of CD4-cells
to bone marrow may be considered as a general phenomenon in any severe
and persistent hypercortisolism (an excess of cortisol in the blood) in
acute-phase inflammatory reactions in which the whole body responds to
an inflammation or injury.
With regard to the direct effect of hypercortisolism on the lymphocytes,
it has to be considered that immature CD4+/CD8+ cells which are produced
in the thymus (thymocytes) represent the most cortisol-sensitive element
of the lymphatic tissue. They are reduced by increased apoptosis so that
the number of these immature CD4/CD8 cells decreases noticeably. Peripheral
mature CD4+/CD8- and CD4-/CD8+ lymphocytes are relatively cortisol resistant.(11)
One could now ask whether the temporary sequestration of CD4-cells to
the bone marrow during acute-phase reactions can be incorporated into the
general concept of the neuroendocrinal control of the immune system. Mosmann
and Coffman showed in 1986 that the CD4-lymphocytes can be divided into
two cell-groups, known as Th-1 and Th-2 cells (Th is an abbreviation for
T-helper cell).(12) The Th-1 cells secrete mainly Interleukin(IL)-2, IL-12
and Interferon(IFN)-gamma, which are chemical messengers which stimulate
cellular immune reactions. The Th-2 cells secrete mainly IL-4, IL-6 and
IL-10 which stimulate the humoral immune reactions.
The significant step towards clarification of the mechanisms behind
production of these chemical messengers known as cytokines was made by
the study group around Daynes.(13,14) This group revealed first of all
that regulation of the cytokine production of activated lymphocytes takes
place in the periphery. Mitogen (a substance which activates cells to divide)-
or antigen-stimulated lymphocytes from lymphoid organs of the mucus membranes
produce mainly IL-4. Lymphocytes from internal organs produce mainly IL-2.
The decisive factor for the type of peripheral regulation of lymphocyte
cytokine production is the production of steroid hormones which are produced
locally from inactive precursors. In this process the dehydroepiandrostosterone
(DHEA) produced in the cortex of the adrenal glands plays an important
role as an antagonist to cortisol. DHEA is the adrenocortical hormone contained
in the blood in the highest concentration of all the steroid hormones.
In its sulphated form, DHEAS, it is inactive. By means of steroid sulphatase,
DHEAS is desulphated in the periphery and thus transformed into DHEA, the
active form. In the lymphocytes the active DHEA causes increased production
of IL-2 and IFN-gamma, 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-1 and/or Th-2 CD4-lymphocytes.
In the lymphatic tissue the macrophages are the only cells that have
an appreciable quantity of DHEAS sulphatase. Moreover the high concentration
of circulating DHEAS is used for the production of androgenic (male sex)
and secondarily of oestrogenic (female sex) hormones.
After what has been said it seems plausible to us to consider the sequestration
of CD4-lymphocytes to the bone marrow as a significant component of a stress-induced
Th-2 profile of CD4-lymphocytes, because in the Th-2 profile in the bone
marrow CD4-cells actively stimulate the B-cells, present there in large
numbers, to increase the formation of antibodies.
If one looks into this question further one finds four studies by Fauci
et al who, during 1976 and 1977, drew attention to the fact that
in the case of cortisol-induced sequestration of CD4-cells into the bone
marrow, these stimulate the B-cells to increase antibody production. In
these studies they anticipated many findings regarding the Th-1 and Th-2
cytokine profiles of CD4-lymphocytes.(15-18)
In order to support our still hypothetical notions it seems to us to
be useful to analyse the course of the CD4/CD8 ratio in the transition
phase from HIV infection to the development of AIDS together with other
parameters for this acute phase reaction, e.g. the body’s own bioactive
cortisol content or the C-reactive protein content. Following a suggestion
by Cottier, in these patients we recommend that the size of the thymus
be measured regularly by means of an imaging procedure such as nuclear
In conclusion we would point out that studies of sequestration of CD4-cells
in bone marrow can provide a clue to the question of long-term survival
of individuals judged to be infected with HIV. They may have overcome HIV
infection not exclusively by cellular immune reactions as in immunologically
healthy persons, but with an additional humoral response in which the production
of anti-HIV antibodies has occurred. They then remain in the neuroendocrine
Th-1 state and do not induce the transformation into the Th-2 state along
with the hypercortisolism required for the development of AIDS, thus sparing
the patients this disease. *
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and Cancer Chemotherapy by a Novel flow Immunocytometric Method. Blood,
2. T.H. Finkel, et al.: Apoptosis occurs predominantly
in Bystander cells and not in productively infected cells of HIV- and SIV-infected
lymph nodes. Nature Medicine, 1:129-134 (1995).
3. G. Pantaleo & A.S. Fauci: Apoptosis in HIV infection.
Nature Medicine, 1:118-120 (1995).
4. A.S. Fauci & D.C. Dale: The effect of in vivo hydrocortisone
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19. H. Cottier: personal communication.
This paper was offered to Nature Medicine, but after some
deliberation they refused to publish it.