Since early in the AIDS epidemic, HIV-infected individuals have higher incidence rates of Kaposi's sarcoma (ICS) than HIV-1 infected age-matched controls. Among HIV-infected individuals with KS, a clinical staging system presented unique challenges because of the multifocal presentation without a defined primary site, and because the severity of HIV-infection independently influences the growth and proliferation of KS spindle cells. We recently identified circulating cells that shared phenotypic and functional properties with the spindle cells of KS lesions. The cells were high inpatients with KS and HIV-infected individuals at highest risk to develop KS. Moreover, we recently discovered that these cells are infected with the proposed etiologic agent of KS, human herpesvirus 8 (HHV-8) and that transcripts for a viral homologue of cellular cyclin D are found in these cells. These findings led us to the following hypothesis that will be tested as part of a multi-institutional Eastern Cooperative Oncology Group A1DS-KS Phase III study evaluating Paclitaxel versus liposomal Doxorubicin in Advanced AIDS-associated KS. The working hypothesis to be tested is that Kaposi's sarcoma initiation requires human herpesvirus 8 infection of an endothelial progenitor cell.
In specific aim 1, `we will quantitate the number of endothelial progenitor cells cultured from AIDS-KS patients before therapy and determine if this number has Prognostic value in assessing survival and response to therapy. Peripheral blood mononuclear cells will be cultured using defined culture conditions and the number of VE-cadherin+CD34+ cells will be determined after 10 days in culture. These values will be compared with CD4 lymphocyte count and extent of skin lesions.
In aim 2, we will determine if the increased numbers of endothelial progenitors before therapy correlate with a high baseline HIV viral load. In the third aim, we will utilize a well-characterized HHV-8 v-cyclin D antibody to identify HHV-8-infected cells in the peripheral blood of AIDS-KS patients. strategy will be used to determine if the infected cells are stem cells or lineage committed cells. The results from these studies will advance our knowledge of KS pathogenesis, HHV-8 viral tropism, and hopefully improve our staging and ability to monitor AIDS-KS disease response.
