CD34+ PROGENITOR IN PATHOGENESIS OF AIDS KAPOSI SARCOMA

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AIDS associated Kaposi's Sarcoma (AIDS-KS) is still one of the major AIDS associated pathologies in HIV infected homosexuals. AIDS-KS tumors are multifocal angiogenic lesions formed by neovasculature and spindle shaped cells. These spindle shaped cells have markers for endothelial cells, smooth muscle cells and dermal dendrocytes and are the "tumor cell" in KS; however these cells don't form tumors when injected in nude mice and it has not been firmly establish whether they are transformed. Two major issues are still unresolved l) What is the progenitor cell type and what factors drive these cells to KS 2) Are KS cells transformed or are they normal cells driven to a proliferative angiogenic phenotype, and if they are transformed, what are the transforming agents? Recently, circulating cells resembling KS in patients with this disorder have been described, and a DNA fragment from a new class of herpes virus associated with a very high percentage of AIDS-KS (KSHV) lesions has been isolated. In preliminary studies, a model to study the development of circulating normal human CD34+ progenitors cells into spindle shaped cells resembling KS-cells, and to endothelium was established. It was found that T-cell cytokines affect CD34+ differentiation and a cell line containing the KSHV DNA can alter both the normal development of CD34+ progenitors and virally-transmit KSHV DNA to umbilical cord blood mononuclear cells. We postulate that the AIDS-KS precursor is a normal CD34+ circulating cell and that KS is the result of an alteration of the development in the CD34+ precursor caused directly by viral transformation (KSHV) or indirectly by cytokine mediators. To test this hypothesis we will expose CD34+ cell populations enriched in KS progenitors to KSHV and HIV infection; or to the T-cell cytokines released in response to those infections. We will examine the ability of the CD34-derived KS-like cells and KSHV infected cells in their ability to support angiogenesis in vitro and to induce KS-lesions in vivo; and the ability to form colonies in soft agar and induce tumors in nude mice. The circulating KS progenitor will be isolated and its phenotypical markers and behavior in vitro and in vivo will be studied. The results of this study will provide important insights into the pathogenesis of AIDS-KS and will foster development of novel mechanistic and intervention studies for AIDS-KS.