VIRAL PERSISTENCE--GENETIC AND IMMUNOLOGICAL STUDIES

这些研究的长期目标是了解病毒是如何持续存在的 并在整个动物水平上造成免疫抑制。尽管 我们关于结构和复制的知识取得了显著的进展 在许多不同的病毒中，病毒持续存在的机制和 对免疫系统的损害仍然知之甚少。小鼠的感染 为淋巴细胞性脉络膜脑膜炎病毒(LCMV)提供了体内模型 为研究该病毒与猪免疫系统之间的相互作用 它的自然宿主，以及定义导致病毒清除的条件 或是坚持不懈。由体内精选的LCMV变种组成的广泛小组 嗜巨噬细胞、嗜淋巴细胞或嗜两性的 被隔离了。与亲本LCMV株相比，这三个株 变异类型在成年小鼠中建立慢性感染提示 在体内持续存在的能力是由于增强了 巨噬细胞和/或淋巴细胞。这一结论进一步得到了证实。 通过发现变异体和亲本病毒生长得同样好 和观察到的生长差异是特定于细胞的 对免疫系统的影响。这项提议的目标有两个方面： 首先，确定免疫系统趋向性的分子基础 通过识别允许病毒在巨噬细胞或 淋巴细胞，并分析这些突变如何影响细胞的功能- 具体的方式。第二，确定病毒细胞的重要性 免疫抑制中的趋向性。我们将做一些实验来分析 几种独立分离变异体的免疫抑制潜能 以确定淋巴细胞和/或优先感染 巨噬细胞易受机会性感染。这些 确定细胞嗜性的病毒遗传决定因素的研究和检测 这些取向对持久性和免疫抑制的影响 在整个动物水平上，应该会导致一个改善的基本 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.