EVOLUTION OF AN ACUTELY LETHAL SIV

致命性 SIV 的进化

• 批准号: 2672111
• 负责人: Patricia N Fultz
• 金额: $ 31.03万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-04-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2672111
• 关键词: Macaca; apoptosis; biochemical evolution; biological signal transduction; gene mutation; interleukin 6; leukocyte activation /transformation; lymphocyte; molecular cloning; nucleic acid sequence; simian AIDSs; simian immunodeficiency virus; tissue /cell culture; tumor necrosis factor alpha; virulence; virus protein

DESCRIPTION: There is increasing evidence that chronic activation of the immune system may be a major factor leading to AIDS and paradoxically to its complete failure. From initial infection to late-stage HIV disease multiple signs of activation involving all lymphocyte subsets have been documented. To address problems associated with lentiviral disease, infection of macaques with the related simian immunodeficiency virus (SIV) is the most appropriate model system. Using a family of highly related SIV strains with defined biologic properties that induce a spectrum of disease in macaques, the investigators propose to identify: 1) signal transduction pathways activated in macaque lymphocytes after SIV infection; 2) the mechanism of apoptosis associated with SIV infection; 3) the roles of SIV Nef and Env proteins in cellular activation, apoptosis and disease progression; and 4) specific genes or regions of the SIV genome that influence viral pathogenesis during evolution of the quasispecies. A combination of in vitro and in vivo techniques, such as immunofluorescence, radioimmunoprecipitation, immunohistochemistry and in situ hybridization, to assess the expression of specific cellular genes during SIV infection will be used. Other studies include PCR-mediated analyses of mRNA expression of cellular proteins; transfection of cells with vectors expressing SIV Nef and Env proteins; sequence analysis of specific regions in SIV proviral DNA and genomic RNA in tissues obtained during persistent infection of macaques; evaluation of the effects of changes in regions of the SIV genome on pathogenesis. These studies will test the hypothesis that HIV/SIV and their antigens interfere with normal cellular signal transduction pathways, leading to uncontrolled immune system activation and ultimately to increased viral burden, pathogenicity, anergy and cell death.

描述：越来越多的证据表明，慢性激活 免疫系统可能是导致艾滋病的一个主要因素，但矛盾的是，它也导致了艾滋病的发生。 彻底失败。 从最初感染到晚期艾滋病毒多重感染 涉及所有淋巴细胞亚群的激活迹象已被记录。 为了解决与慢病毒疾病、感染相关的问题 携带相关猿猴免疫缺陷病毒（SIV）的猕猴是最常见的 适当的模型系统。 使用高度相关的 SIV 毒株家族 确定了诱发猕猴一系列疾病的生物学特性， 研究人员建议确定：1）信号转导途径 SIV感染后在猕猴淋巴细胞中被激活； 2）机制 与SIV感染相关的细胞凋亡； 3）SIV Nef和Env的作用 细胞激活、细胞凋亡和疾病进展中的蛋白质；和 4) SIV 基因组中影响病毒的特定基因或区域 准种进化过程中的发病机制。 的组合在 体外和体内技术，例如免疫荧光， 放射免疫沉淀、免疫组织化学和原位杂交 评估 SIV 感染期间特定细胞基因的表达 被使用。 其他研究包括 PCR 介导的 mRNA 表达分析 细胞蛋白质；用表达 SIV Nef 的载体转染细胞 包膜蛋白； SIV 前病毒 DNA 中特定区域的序列分析和 在猕猴持续感染过程中获得的组织中的基因组RNA； 评估 SIV 基因组区域变化的影响 发病。 这些研究将检验 HIV/SIV 及其相关病毒的假设 抗原干扰正常的细胞信号转导途径， 导致免疫系统激活失控并最终增加 病毒负荷、致病性、无反应性和细胞死亡。