PATHOGENESIS OF HUMAN IMMUNODEFICIENCY VIRUS 1 (HIV-1)

这些研究的目的是探讨细胞外的作用， 基质蛋白及其受体在艾滋病发病机制中的作用 最近 工作集中在HIV相关肾病， 被认为是感染HIV-1的并发症，特别是在 非裔美国人 虽然病理学已经得到了很好的表征， HIV诱发肾脏疾病的机制在很大程度上 未知 为了解决这个问题，我们建立了一种转基因小鼠， 使用HIV-1前病毒DNA的模型，通过3 kb缺失使其不具有感染性 与gag和pol基因重叠。 这种结构包含病毒 LTRs和编码包膜糖蛋白以及调节和 辅助基因 杂合子小鼠发生肾病基本上 与HIV相关性肾病一致 肾小球硬化和肾小管间质疾病。 这些发现 支持病毒蛋白在AIDS发病机制中重要作用。 作为 因此，我们目前正在探索肾细胞是否可以维持 生产性感染以及HIV-1感染细胞如何靶向肾脏 组织中 我们发现感染细胞表达表面粘附 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 细胞表面粘附受体，附着在基底膜上， 释放促进组织侵入的蛋白酶。 目前的研究是 目的在于开发新的HIV-1转基因株系， 在组织特异性启动子控制下的基因， 在我们目前的转基因系中的治疗性构建体，以及新的 治疗策略，包括系统性反义和HIV-1靶向 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.