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Pathogenesis of aids kaposi's sarcoma: biological, clinical and therapeutic aspects

Objective

To synergize European research capabilities in the field of AIDS associated Kaposi's sarcoma (KS) pathogenesis, particularly with regard to the importance of HIV-Tat and other angiogenic factors, chorionic gonadotropin hormone (hCG) as a possible regressive factor, the role of the newly discovered KS herpes virus (KSHV/HHV-8) and possible development of antiviral therapy as well as the use of animal models.

BACKGROUND AND OBJECTIVES:

Kaposi's sarcoma (KS), previously regarded as a rare, indolent, usually cutaneous tumor-like lesion, has become a serious public health problem through its frequent association with AIDS in all areas of the pandemic. Recent studies on the development of KS have suggested a role for various pathogenic factors including infection with a novel herpes virus (HHV-8), a deregulated cytokine-growth factor network, HIV associated angiogenic factor(s) (Tat) and immune deficiency, hormonal influence and possibly genetic aberrations. Also the apparently partly tumor-like, partly reactive KS features reflect the complexity and still enigmatic biological nature of this lesion. The proposed research concentration addresses to questions of the importance of various factors suggested from recent studies.

The different tasks to be investigated in this proposal will cover the following objectives/aspects:
A) HIV-1 Tat protein as an angiogenic factor in the development of AIDS Kaposi's sarcoma (AKS);
B) Animal models of angiogenesis and Kaposi's sarcoma;
C) Chorionic gonadotropin hormone (hCG) as a repressive factor in KS development;
D) Development of an in vitro model system to study the pathogenic role of HHV-8 in Kaposi's sarcoma;
E) In vitro characterization of HHV-8 infected KS cells, their angiogenic and tumorigenic properties and the possible activation of HHV-8 in iatrogenic immunosuppressed patients;
F) Studies on the presence of HHV-8 in PBMC, semen and tissues of immuno- suppressed and KS patients;
G) Demonstration of possible DNA aberrations in Kaposi's sarcoma by comparative genomic hybridisation.(CGH);
H) Development of serological assays for KSHV/HHV-8 and determining its prevalence in different European populations;
I) Search for antiviral drugs against HHV-8.

IMPLEMENTATION OF STUDIES: The tasks necessitate the share and exploitation of various biological materials (tissue cultures, biopsies, DNA/RNA extracts and probes) as well as various methods and advanced equipment available to the different laboratories (institutions). Most of the studies will be based on methods for evaluation of the histology, cytology, immunocytochemistry, virology, molecular biology and/or serology of human and animal specimens available as historical or prospective material. The involved responsible participants represent an unique European concentration of complementary research expertise and capabilities in this relatively new field of research dominated by several of the participating laboratories.

IMPORTANCE: The studies are expected to significantly clarify basic questions of the relative importance of various pathogenic factors in the evolution of KS, including the geographic prevalence and prognostic importance of HHV-8, the role of Tat, hormonal factors and the question of possible genetic aberrations and tumor nature of KS. Results from these studies may lead to considerations of diagnostic screening of blood donors for HHV-8, as well as immuno-suppressed patients at risk for developing KS. Results of the genomic studies on HHV-8will allow considerations of the possible production of antiviral compounds specific for HHV-8.

Funding Scheme

CON - Coordination of research actions

Coordinator

Karolinska Institute
Address

171 76 Stockholm
Sweden