GAMMA-INTERFERON PRODUCED BY CD8(-CELLS INFILTRATING KAPOSIS-SARCOMA INDUCES SPINDLE CELLS WITH ANGIOGENIC PHENOTYPE AND SYNERGY WITH HUMANIMMUNODEFICIENCY VIRUS-1 TAT PROTEIN - AN IMMUNE-RESPONSE TO HUMAN-HERPESVIRUS-8 INFECTION() T)

Kaposi's sarcoma (KS) is an angioproliferative disease associated with infection by the human herpesvirus-8 (HHV-8). HHV-8 possesses genes i ncluding homologs of interleukin-8 (IL-8) receptor, Bcl-2, and cyclin D, which can potentially transform the host cell. However, the express ion 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 a lso through indirect mechanisms. Evidence suggests that KS may start a s an inflammatory-angiogenic lesion mediated by cytokines. However, li ttle is known on the nature of the inflammatory cell infiltration pres ent 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 t hat 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 gamma-interferon (gamma IFN) which, in turn, promotes the formation of KS spindle cells with angiogenic phenotype. gamma IFN, in fact, induces endothelial cells to acquire the same features of KS cells, including the spindle morpholo gy and the pattern of cell marker expression. In addition, endothelial cells activated by gamma IFN induce angiogenic lesions in nude mice c losely resembling early KS. These KS-like lesions are accompanied by p roduction of basic fibroblast growth factor, an angiogenic factor high ly expressed in primary lesions that mediates angiogenesis and spindle cell growth. The formation of KS like lesions is upregulated by the h uman immunodeficiency virus Tat protein demonstrating its role as a pr ogression factor in AIDS-KS. Finally, gamma IFN and HLA-DR expression correlate with the presence of HHV-8 in lesional and uninvolved tissue s from the same patients. As HHV-8 infects both mononuclear cells infi ltrating KS lesions and KS spindle cells, these results suggest that H HV-8 may elicit or participate in a local immune response characterize d by infiltration of CD8(+) T cells and intense production of gamma IF N which, in turn, plays a key role in KS development. (C) 1998 by The American Society of Hematology.