EVOLUTION OF AN ACUTELY LETHAL SIV

描述：有越来越多的证据表明，慢性激活的 免疫系统可能是导致艾滋病主要因素， 彻底失败 从最初感染到晚期艾滋病毒疾病多重 涉及所有淋巴细胞亚群的活化迹象都有记载。 为了解决与慢病毒病相关的问题， 猕猴与相关的猿猴免疫缺陷病毒（SIV）是最 合适的模型系统。 使用高度相关的SIV毒株家族， 在猕猴中引起一系列疾病的生物学特性， 研究人员提出要确定：1）信号转导途径 SIV感染后猕猴淋巴细胞中的激活; 2） SIV感染与细胞凋亡的关系; 3）SIV Nef和Env的作用 细胞活化、凋亡和疾病进展中的蛋白质;以及4） SIV基因组中影响病毒的特定基因或区域 准种进化过程中的致病机制。 一个结合在 体外和体内技术，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感染过程中特定细胞基因的表达， 被利用 其他研究包括PCR介导的mRNA表达分析， 用表达SIV Nef的载体转染细胞， SIV前病毒DNA中特定区域的序列分析， 猕猴持续感染期间获得的组织中的基因组RNA; 评价SIV基因组区域变化对 发病机制 这些研究将检验艾滋病毒/SIV及其 抗原干扰正常的细胞信号转导途径， 导致不受控制的免疫系统激活， 病毒负荷、致病性、无能和细胞死亡。

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.