HIV-INFECTED GI MESENCHYMAL CELLS MIMIC KAPOSI'S SARCOMA

人类免疫缺陷病毒1型(HIV-1)的作用机制 卡波西肉瘤(KS)血管细胞的发育与调控 KS病变形成过程中的生长尚不清楚。这是 部分原因是这种疾病的体外模型 到目前为止有限，主要集中在KS来源的细胞 在启动事件发生后很久才发生的损害。我们 最近发现人类胃肠道(GI)感染 粘膜下间充质(SM)细胞(包括血管细胞和 血管细胞前体)与HIV-1一起导致细胞群体 生长特性异常，内皮细胞合成增加， 血管母细胞标志物和血管生成因子的释放。基于这些 观察到，我们目前的假设是HIV-1感染血管 和来自胃肠道间充质组织的其他细胞是 血管生成的启动事件、诱导和其他特征 KS的发展。本申请的目的是追求这一点 本RFA框架内的假设，实现以下几点 具体目标：[1]培养、克隆和鉴定血管和其他 SM来源的细胞；[2]测试各种HIV毒株以鉴定毒株- 传染性在个体之间的具体差异，胃肠道器官部位， 或诱导KS样表型；[3]比较生长 细胞的特性、血管生成和致瘤特性 接种HIV疫苗后控制培养物和KS来源的培养物 损伤；[4]检测在合成或反应方面的任何差异， 生长控制分子；[5]确定TAT基因产物是否可以 直接导致SM细胞的行为类似于KS细胞；[6]评估 微生物辅助因子(特别是巨细胞病毒和支原体)在 调节病毒复制和/或KS表型。这些研究已经 主要的潜在含义不仅是对生物学的理解 KS的发展，但也有多个方面的增长和 在这个模型系统中，血管细胞的分化受到调控。 这种工作可能会导致潜在的预防或治疗应用 这种通常与艾滋病有关的疾病以及 心血管疾病。

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.