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 -Interferon Produced by CD8+ T Cells Infiltrating
Kaposi's Sarcoma Induces Spindle Cells With Angiogenic Phenotype and
Synergy With Human Immunodeficiency Virus-1 Tat Protein: An Immune
Response to Human Herpesvirus-8 Infection?
Valeria Fiorelli,
Rita Gendelman,
Maria Caterina Sirianni,
Hsiao-Kuey Chang,
Sandra Colombini,
Phillip D. Markham,
Paolo Monini,
Joseph Sonnabend,
Aldo Pintus,
Robert C. Gallo, and
Barbara Ensoli
From the Department of Allergy and Clinical Immunology, University of
Rome "La Sapienza," Rome, Italy; the Laboratory of Tumor Cell
Biology, National Cancer Institute, National Institutes of Health,
Bethesda, MD; the Institute of Human Virology, University of Maryland
at Baltimore, Baltimore, MD; Advanced BioScience Laboratories, Inc,
Kensington, MD; Laboratory of Virology, Istituto Superiore di Sanita',
Rome, Italy; Community Research Initiative on AIDS New
York; Istituto Di Clinica Medica, Cattedra Di Genetica,
Cagliari, Italy.
Kaposi's sarcoma (KS) is an angioproliferative disease associated
with infection by the human herpesvirus-8 (HHV-8). HHV-8 possesses
genes including homologs of interleukin-8 (IL-8) receptor, Bcl-2, and
cyclin D, which can potentially transform the host cell. However, the
expression of these genes in KS tissues is very low or undetectable and
HHV-8 does not seem to transform human cells in vitro. In addition, KS
may not be a true cancer at least in the early stage. This indicated
that besides its transforming potential, HHV-8 may act in KS
pathogenesis also through indirect mechanisms. Evidence suggests that
KS may start as an inflammatory-angiogenic lesion mediated by
cytokines. However, little is known on the nature of the inflammatory
cell infiltration present in KS, on the type of cytokines produced and
on their role in KS, and whether this correlates with the presence of
HHV-8. Here we show that both acquired immunodeficiency syndrome
(AIDS)-KS and classical KS (C-KS) lesions are infiltrated by
CD8+ T cells and CD14+/CD68+
monocytes-macrophages producing high levels of  -interferon (IFN) which, in turn, promotes the formation of KS spindle cells with angiogenic phenotype. IFN, in fact, induces endothelial cells to
acquire the same features of KS cells, including the spindle morphology
and the pattern of cell marker expression. In addition, endothelial
cells activated by IFN induce angiogenic lesions in nude mice
closely resembling early KS. These KS-like lesions are accompanied by
production of basic fibroblast growth factor, an angiogenic factor
highly expressed in primary lesions that mediates angiogenesis and
spindle cell growth. The formation of KS-like lesions is upregulated by
the human immunodeficiency virus Tat protein demonstrating its role as
a progression factor in AIDS-KS. Finally, IFN and HLA-DR expression
correlate with the presence of HHV-8 in lesional and uninvolved tissues
from the same patients. As HHV-8 infects both mononuclear cells
infiltrating KS lesions and KS spindle cells, these results suggest
that HHV-8 may elicit or participate in a local immune response
characterized by infiltration of CD8+ T cells and intense
production of IFN which, in turn, plays a key role in KS
development.
Blood, Vol. 91 No. 3 (February 1), 1998:
pp. 956-967
© 1998 by The American Society of Hematology.
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