Mechanisms by which human immunodeficiency virus-1 (HIV-1) is involved in Kaposi's sarcoma (KS) development and regulation of vascular cell growth in the formation of a KS lesion are not understood. This is partially due to the fact that in vitro models for the disease have thusfar been limited, and primarily focused on cells derived from KS lesions which occur long after the initiating events have occurred. We have recently found that infection of human gastrointestinal (GI) submucosal mesenchymal (SM) cells (which includes vascular cells and vascular cell precursors) with HIV-1 led to cell populations with abnormal growth properties, increased synthesis of endothelial cell and angioblast markers, and release of angiogenic factors. Based on those observations, our current hypothesis is that HIV-1 infection of vascular and other cells derived from GI mesenchymal tissue is a model for the initiation events, induction of angiogenesis, and other features of the development of KS. The purpose of this application is to pursue that hypothesis within the framework of this RFA by achieving the following specific aims: [1] Culture, clone, and characterize vascular and other SM-derived cells; [2] Test various strains of HIV to identify strain- specific differences in infectivity among individuals, GI organ sites, or induction of the KS-like phenotype; [3] Compare the growth characteristics, angiogenic and tumorigenic properties of the cells after HIV inoculation to control cultures and cultures derived from KS lesions; [4] Detect any differences in the synthesis of, or response to, growth-controlling molecules; [5] Determine if the tat gene product can directly cause SM cells to behave like KS cells; [6] Assess the role of microbiological co-factors (particularly CMV and Mycoplasma) in modulating virus replication and/or the KS phenotype. These studies have major potential implications towards understanding not only the biology of KS development, but also multiple facets by which the growth and differentiation of vascular cells is regulated in this model system. Such work may lead to potential applications for prevention or treatment of this affliction which is commonly associated with AIDS as well as cardiovascular diseases.
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