EVOLUTION OF AN ACUTELY LETHAL SIV

描述：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的一个主要因素，而矛盾的是，它 彻底失败了。从最初的感染到晚期的HIV疾病多重 涉及所有淋巴细胞亚群的激活迹象已被记录在案。 为了解决与慢病毒病相关的问题，感染 与猴免疫缺陷病毒(SIV)相关的猕猴是最多的 适当的模式体系。使用一组高度相关的SIV毒株 明确的生物学特性会导致猕猴的一系列疾病， 研究人员建议确定：1)信号转导途径 SIV感染后猕猴淋巴细胞的活化；2)SIV感染的机制 细胞凋亡与SIV感染；3)SIV Nef和Env的作用 参与细胞激活、凋亡和疾病进展的蛋白质；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。中的组合 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。其他研究包括聚合酶链式反应介导的基因表达分析。 细胞蛋白.用表达SIV Nef和SIV Nef和SIV Nef的载体转染细胞 SIV前病毒DNA中特定区域的序列分析和 恒河猴持续感染过程中组织中的基因组RNA； 评价SIV基因组区域变化对人类免疫功能的影响 发病机制。这些研究将检验艾滋病毒/SIV和他们的 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，最终导致 病毒负担、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.