Our arsenals for fighting off bacteria are so powerful, and
involve so many different defense mechanisms, that we are in more
danger from them than the invaders. We live in the midst of explosive
devices; we are mined.
--Lewis Thomas, MD
The Lives of a Cell
Although the late Dr. Thomas was actually referring to bacterial
sepsis, his statement could easily have applied to the cytokine
"storm" of HIV infection and Kaposi's sarcoma (KS).
This cytokine dysregulation, nicely described in the article by
the UCLA group, is one of the major culprits responsible for the
proliferation of KS in HIV-infected patients. The abnormally high
cytokine levels are produced not only by HIV infection and opportunistic
and nonopportunistic infections but also by the KS cells themselves.
The paracrine and autocrine effects of these cytokines can lead
to both the development of KS lesions and the proliferation of
preexisting lesions. The tremendous synergy between cytokines
and the HIV tat protein provides a possible insight into why AIDS-related
KS (AIDS/KS) is much more virulent than the classic Mediterranean
form of KS in older men, in which HIV tat protein would not be
expected to play any role.
Two Important Clinical Scenarios
Two important clinical scenarios, in particular, need to be kept
in mind, given the prominent role that cytokine dysregulation
plays in the pathogenesis of KS. The first scenario is that of
corticosteroid therapy, which has been associated with the induction
of KS and with the exacerbation of preexisting KS in HIV-infected
persons [1,2], as well as in non-AIDS patients, such as those
receiving steroids for organ transplantation, autoimmune disorders,
or lymphoproliferative diseases . Steroid use is not uncommon
in HIV-infected patients, who have a variety of disorders, including
immune thrombocytopenic purpura and Pneumocystis carinii
pneumonia. Kaposi's sarcoma lesions may regress upon reduction
or withdrawal of steroids [1-3]. The laboratory correlate of these
clinical observations is the in vitro stimulation of AIDS/KS cells
by dexamethasone . Furthermore, simultaneous exposure to dexamethasone
and oncostatin-M (Onco-M), a major cytokine involved in the pathogenesis
of KS, produces a dramatic synergistic effect on the proliferation
of AIDS/KS cells, suggesting an interaction between glucocorticoid
and growth factor intracellular pathways in these cells .
The second scenario is that of opportunistic infections, which
also have been associated with the induction of KS and with the
exacerbation of preexisting KS similar to that described above
with corticosteroid therapy. As the authors note, high levels
of tumor necrosis factor-alpha (TNF- alpha), interleukin-1
beta (IL-1 beta), and interleukin-6 (IL-6), which have been demonstrated
in the setting of opportunistic infections, may account for the
above-mentioned effects on KS. High levels of IL-6 have been found
in patients with KS and may precede the development of the disease
in HIV-infected men .
Finally, the recent demonstration of sequences of the KS-associated
herpes virus (KSHV) in KS lesions is truly a seminal observation
. This striking association has quelled much of the previous
controversy regarding the roles of cytomegalovirus, Epstein-Barr
virus, human papilloma virus, mycoplasma, and inhaled nitrites
in the pathogenesis of KS. As aptly stated by the authors, the
exact role of KSHV in the pathogenesis of KS will require further
research--an extraordinary tale that we will eagerly follow as
Plausible Model of Pathogenesis
The authors' model of the pathogenesis of KS is plausible. In
brief, they suggest the following steps in pathogenesis:
- transformation of normal mesenchymal cells to a "pre-KS"
cell by KSHV;
- proliferation and differentiation of the KS tumor stimulated
by the cytokine dysregulation brought on by HIV infection, opportunistic
and nonopportunistic infections, and the KS cells themselves;
- further proliferation of the KS tumor induced by the synergy
between cytokines and the HIV tat protein and, in certain clinical
settings, by the synergy between cytokines and exogenous steroids;
- transformation of KS into a more malignant phenotype as HIV
induces greater immunosuppression and as tumors enlarge.
This model of a progressively aggressive tumor may explain
why KS is contributing more and more to both morbidity and mortality
in HIV-infected individuals as they live for progressively longer
. New treatments based on the pathogenesis of KS, as the authors
note, are a direct consequence of this model; these treatments
involve inhibition of KSHV, inhibition of cytokine production
or blockade of cytokine receptors, inhibition of angiogenesis,
and blockade of intracellular signal transduction.
1. Gill PS, Loureiro C, Bernstein-Singer M, et al: Clinical effect
of glucocorticoids on Kaposi sarcoma related to the acquired immunodeficiency
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2. Medrano FJ, Aguado I, Andreu J, et al: Steroid-related bronchopulmonary
Kaposi's sarcoma in a homosexual man with AIDS (abstract). Programs
and Abstracts of the 7th International Conference on AIDS, p 218,
3. Trattner A, Hodak E, David M, et al: The appearance of Kaposi
sarcoma during corticosteroid therapy. Cancer 72:1779-1783, 1993.
4. Guo W-X, Antakly T: AIDS-related Kaposi's sarcoma: Evidence
for direct stimulatory effect of glucocorticoid on cell proliferation.
Am J Pathol 146:727-734, 1995.
5. Martinez-Maza O, Dourado I, Kishimoto T, et al: Elevated serum
interleukin-6 levels are associated with the development of AIDS-Kaposi's
sarcoma (abstract). Programs and Abstracts of the 9th International
Conference on AIDS, p 397, Berlin, 1993.
6. Chang Y, Cesarman E, Pessin MS, et al: Identification of herpesvirus-like
DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266:1865-1869,
7. Peters BS, Beck EJ, Coleman DG, et al: Changing disease patterns
in patients with AIDS in a referral centre in the United Kingdom:
The changing face of AIDS. Br Med J 302:203-206, 1991.