CD34+ PROGENITOR IN PATHOGENESIS OF AIDS KAPOSI SARCOMA

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date9/30/958/31/01

Funding

  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases

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