PATHOGENESIS OF HUMAN IMMUNODEFICIENCY VIRUS 1 (HIV-1)

这些研究的目的是探索细胞外的作用 基质蛋白及其受体在艾滋病发病机制中的作用近期 工作的重点是艾滋病毒相关的肾病，它越来越多地 被认为是感染艾滋病毒-1的并发症，特别是在 非裔美国人。尽管病理特征很清楚， 艾滋病毒导致肾脏疾病的机制在很大程度上仍然存在 未知。为了解决这个问题，我们建立了一只转基因小鼠 使用HIV-1前病毒DNA通过3kb缺失而变得非传染性的模型 GAG和POL基因重叠。该结构包含病毒 Ltrs和编码包膜糖蛋白以及调节和 附属基因。杂合子小鼠本质上会患上肾脏疾病 局灶性节段性肾病患者与HIV相关性肾病相同 肾小球硬化和肾小管间质疾病。这些发现 支持病毒蛋白在艾滋病发病机制中的重要作用。AS 因此，我们目前正在探索肾脏细胞是否能够维持 生殖性感染和HIV-1感染细胞如何靶向肾脏 纸巾。我们发现被感染的细胞表现出表面黏附。 识别内皮和基底膜蛋白的分子。我们 还发现感染HIV-1的T细胞和巨噬细胞表达 细胞表面黏附受体，附着于基底膜，以及 释放促进组织侵入的蛋白酶。目前的研究是 为培育新的单基因HIV-1转基因株系奠定基础 基因控制下的组织特异性启动子、基因检测 我们目前的转基因系中的治疗性结构，以及新的 包括系统反义和HIV-1靶向治疗的策略 核酶。

The objective of these studies is to explore the role of extracellular matrix proteins and their receptors in the pathogenesis of AIDS. Recent work has focused on HIV-associated nephropathy which is increasingly recognized as a complication of infection with HIV-1, particularly among African Americans. Although the pathology has been well-characterized, the mechanisms by which HIV induces renal disease remains largely unknown. To address this issue, we have established a transgenic mouse model using HIV-1 proviral DNA rendered non-infectious by a 3 kb deletion overlapping the gag and pol genes. This construct contains the viral LTRs and encodes envelope glycoproteins as well as regulatory and accessory genes. Heterozygous mice develop renal disease essentially identical to HIV associated nephropathy in man with focal segmental glomerulosclerosis and tubulointerstitial disease. These findings support an important role for viral proteins in AIDS pathogenesis. As a result, we are currently exploring whether renal cells can sustain productive infection and how HIV-1 infected cells can target renal tissues. We have found that infected cells express surface adhesion molecules that recognize endothelium and basement membrane proteins. We have also found that T-cells and macrophages infected with HIV-1 express cell surface adhesion receptors, attach to basement membranes, and release proteases that facilitate tissue invasion. Current studies are directed to the development of new HIV-1 transgenic lines with single genes under the control of tissue-specific promoters, the testing of gene therapeutic constructs in our current transgenic lines, and new strategies for therapy including systemic antisense and HIV-1-targeted ribozymes.