Pathogenesis of AIDS-Related Kaposi's Sarcoma

March 1, 1996
Bruce J. Dezube, MD
Bruce J. Dezube, MD

Volume 10, Issue 3

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.

Our arsenals for fighting off bacteria are so powerful, andinvolve so many different defense mechanisms, that we are in moredanger from them than the invaders. We live in the midst of explosivedevices; we are mined.

--Lewis Thomas, MD
The Lives of a Cell

Although the late Dr. Thomas was actually referring to bacterialsepsis, 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 bythe UCLA group, is one of the major culprits responsible for theproliferation of KS in HIV-infected patients. The abnormally highcytokine levels are produced not only by HIV infection and opportunisticand nonopportunistic infections but also by the KS cells themselves.

The paracrine and autocrine effects of these cytokines can leadto both the development of KS lesions and the proliferation ofpreexisting lesions. The tremendous synergy between cytokinesand the HIV tat protein provides a possible insight into why AIDS-relatedKS (AIDS/KS) is much more virulent than the classic Mediterraneanform of KS in older men, in which HIV tat protein would not beexpected to play any role.

Two Important Clinical Scenarios

Two important clinical scenarios, in particular, need to be keptin mind, given the prominent role that cytokine dysregulationplays in the pathogenesis of KS. The first scenario is that ofcorticosteroid therapy, which has been associated with the inductionof KS and with the exacerbation of preexisting KS in HIV-infectedpersons [1,2], as well as in non-AIDS patients, such as thosereceiving steroids for organ transplantation, autoimmune disorders,or lymphoproliferative diseases [3]. Steroid use is not uncommonin HIV-infected patients, who have a variety of disorders, includingimmune thrombocytopenic purpura and Pneumocystis cariniipneumonia. Kaposi's sarcoma lesions may regress upon reductionor withdrawal of steroids [1-3]. The laboratory correlate of theseclinical observations is the in vitro stimulation of AIDS/KS cellsby dexamethasone [4]. Furthermore, simultaneous exposure to dexamethasoneand oncostatin-M (Onco-M), a major cytokine involved in the pathogenesisof KS, produces a dramatic synergistic effect on the proliferationof AIDS/KS cells, suggesting an interaction between glucocorticoidand growth factor intracellular pathways in these cells [4].

The second scenario is that of opportunistic infections, whichalso have been associated with the induction of KS and with theexacerbation of preexisting KS similar to that described abovewith corticosteroid therapy. As the authors note, high levelsof tumor necrosis factor-alpha (TNF- alpha), interleukin-1beta (IL-1 beta), and interleukin-6 (IL-6), which have been demonstratedin the setting of opportunistic infections, may account for theabove-mentioned effects on KS. High levels of IL-6 have been foundin patients with KS and may precede the development of the diseasein HIV-infected men [5].

Finally, the recent demonstration of sequences of the KS-associatedherpes virus (KSHV) in KS lesions is truly a seminal observation[6]. This striking association has quelled much of the previouscontroversy regarding the roles of cytomegalovirus, Epstein-Barrvirus, human papilloma virus, mycoplasma, and inhaled nitritesin the pathogenesis of KS. As aptly stated by the authors, theexact role of KSHV in the pathogenesis of KS will require furtherresearch--an extraordinary tale that we will eagerly follow asit unfolds.

Plausible Model of Pathogenesis

The authors' model of the pathogenesis of KS is plausible. Inbrief, 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 stimulatedby the cytokine dysregulation brought on by HIV infection, opportunisticand nonopportunistic infections, and the KS cells themselves;
  • further proliferation of the KS tumor induced by the synergybetween cytokines and the HIV tat protein and, in certain clinicalsettings, by the synergy between cytokines and exogenous steroids;and
  • transformation of KS into a more malignant phenotype as HIVinduces greater immunosuppression and as tumors enlarge.

This model of a progressively aggressive tumor may explainwhy KS is contributing more and more to both morbidity and mortalityin HIV-infected individuals as they live for progressively longer[7]. New treatments based on the pathogenesis of KS, as the authorsnote, are a direct consequence of this model; these treatmentsinvolve inhibition of KSHV, inhibition of cytokine productionor blockade of cytokine receptors, inhibition of angiogenesis,and blockade of intracellular signal transduction.

References:

1. Gill PS, Loureiro C, Bernstein-Singer M, et al: Clinical effectof glucocorticoids on Kaposi sarcoma related to the acquired immunodeficiencysyndrome. Ann Intern Med 110:937-940, 1989.

2. Medrano FJ, Aguado I, Andreu J, et al: Steroid-related bronchopulmonaryKaposi's sarcoma in a homosexual man with AIDS (abstract). Programsand Abstracts of the 7th International Conference on AIDS, p 218,Florence, 1991.

3. Trattner A, Hodak E, David M, et al: The appearance of Kaposisarcoma during corticosteroid therapy. Cancer 72:1779-1783, 1993.

4. Guo W-X, Antakly T: AIDS-related Kaposi's sarcoma: Evidencefor 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 seruminterleukin-6 levels are associated with the development of AIDS-Kaposi'ssarcoma (abstract). Programs and Abstracts of the 9th InternationalConference on AIDS, p 397, Berlin, 1993.

6. Chang Y, Cesarman E, Pessin MS, et al: Identification of herpesvirus-likeDNA sequences in AIDS-associated Kaposi's sarcoma. Science 266:1865-1869,1994.

7. Peters BS, Beck EJ, Coleman DG, et al: Changing disease patternsin patients with AIDS in a referral centre in the United Kingdom:The changing face of AIDS. Br Med J 302:203-206, 1991.