VIRAL PERSISTENCE--GENETIC AND IMMUNOLOGICAL STUDIES

这些研究的长期目标是了解病毒如何持续存在 并导致整个动物的免疫抑制。 尽管 我们对基因组结构和复制的认识 许多不同的病毒，病毒持续存在的机制， 对免疫系统的损害仍然知之甚少。 感染小鼠 淋巴细胞性脉络丛脑膜炎病毒（LCMV）提供了一种体内模型， 用于研究病毒和免疫系统之间的相互作用， 它的天然宿主，并在定义条件，导致病毒清除 或者坚持 一组广泛的体内选择的LCMV变体 嗜巨噬细胞性、嗜淋巴细胞性或嗜中性粒细胞性， 被孤立。 与亲本LCMV株相比，这三个 变异类型在成年小鼠中建立慢性感染， 在体内持续存在的能力是由于增强的复制， 巨噬细胞和/或淋巴细胞。 这一结论得到进一步加强， 通过发现变异体和亲本病毒同样生长良好， 并且观察到的生长差异是细胞特异性的 免疫系统。 这项建议有两个目的： 首先，确定免疫系统向性的分子基础 通过识别允许病毒在巨噬细胞中持续存在的突变， 淋巴细胞，并分析这些突变如何影响细胞的功能- 具体方式。 第二，确定病毒细胞的重要性 免疫抑制中的向性。 实验将进行分析， 几种独立分离变体的免疫抑制潜力 以确定是否优先感染淋巴细胞和/或 巨噬细胞导致对机会性感染的易感性。 这些 研究确定了病毒的细胞嗜性遗传决定因素， 这些趋向性对持久性和免疫抑制的影响 在整个动物的水平上，应该会导致一个改进的基本 了解慢性病毒感染的免疫发病机制。

The long-term goal of these studies is to understand how viruses persist and cause immune suppression at the whole animal level. Despite the remarkable advances in our knowledge about the structure and replication of many different viruses, the mechanisms by which viruses persist and damage the immune system remain poorly understood. Infection of mice with lymphocytic choriomeningitis virus (LCMV) provides an in vivo model for studying the interaction between the virus and the immune system of its natural host, and in defining conditions that lead to viral clearance or persistence. An extensive panel of in vivo selected LCMV variants that are either macrophage-tropic, lymphocyte-tropic, or amphotropic has been isolated. In contrast to the parental LCMV strain, these three types of variants establish chronic infections in adult mice suggesting that the ability to persist in vivo is due to enhanced replication in macrophages and/or lymphocytes. this conclusion is further strengthened by the finding that the variants and the parental virus grow equally well in fibroblasts and the observed growth differences are specific for cells of the immune system. The objectives of this proposal are two fold: First, to determine the molecular basis of tropism for the immune system by identifying mutations that allow viral persistence in macrophages or lymphocytes, and analyzing how these mutations affect function in a cell- specific manner. Second, to determine the importance of viral cell tropism in immune suppression. Experiments will be done to analyze the immunosuppressive potential of several independently isolated variants to determine whether preferential infection of lymphocytes and/or macrophages results in susceptibility to opportunistic infections. These studies defining viral genetic determinants of cell tropism and examining the consequences of these tropisms for persistence and immune suppression at the whole animal level, should lead to an improved fundamental understanding of the immunopathogenesis of chronic viral infections.