THE ROLE OF LEUKOCYTE SEQUESTRATION IN THE CONTROL OF VIRALINFECTIONS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者的研究机构。 在感染后的一段时间内，许多病毒引起短暂的I型干扰素依赖性淋巴细胞减少症。哺乳动物宿主采取这种策略的原因一直是相当多的猜测的主题，但很少 建议完全令人满意。最近，我们意外地发现，一种淋巴细胞性脉络丛脑膜炎病毒（LCMV）株通常可被免疫活性小鼠迅速清除，阿姆斯特朗菌株引起严重的淋巴细胞减少，但克隆13菌株，建立了高水平的慢性感染，不。为了检验克隆13诱导淋巴细胞减少症的失败与小鼠清除克隆13的失败相关的假设，我们在感染的急性期通过药物FTY 720（一种鞘氨醇类似物，其通过阻断退出所需的信号将淋巴细胞隔离在淋巴器官中）治疗诱导了短暂的淋巴细胞减少症。结果是惊人的：在感染的第0、1和2天，FTY 720的短暂的三天疗程促进了克隆的完全清除。 13，包括肾脏等器官，其中病毒通常持续数月。 然后我们获得了一个可能更重要的结果：在克隆13感染后30天给予FTY 720的短暂过程也诱导了病毒的完全清除。在两个实验中，清除完全依赖于CD 4细胞，表明药物不直接作用于病毒。这些发现提出了一些正在研究的重要问题：探索FTY 720促进LCMV清除的机制;确定FTY 720是否也诱导LCMV诱导的全身免疫抑制的逆转;询问FTY 720是否也改善对其他病毒感染的免疫反应。FTY 720作用于宿主免疫细胞，没有直接的特异性抗病毒作用，可能有助于治疗人类慢性病毒感染，如HIV，HBV或HCV。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the period immediately following infection, many viruses cause a transient, type I interferon-dependent lymphopenia. The reason that mammalian hosts adopt such a strategy has been the subject of considerable speculation, but few proposals have been completely satisfactory. Recently, we made the unexpected discovery that a strain of lymphocytic choriomeningitis virus (LCMV) that is normally rapidly cleared by immmunocompetent micethe Armstrong straininduces a profound lymphopenia, but the clone 13 strain, which establishes a high level chronic infection, does not. In order to test the hypothesis that failure of clone 13 to induce lymphopenia was associated with failure of mice to clear clone 13, we induced transient lymphopenia during the acute phase of infection by treatment with drug FTY720, a sphingosine analog that sequesters lymphocytes in lymphoid organs by blocking signals required for exit. The results were stunning: a transient, three day course of FTY720 at days 0, 1, and 2 of infection promoted complete clearance of clone 13, including from organs such as kidneys where virus normally persists for months. We then obtained a result that is potentially even more important: a transient course of FTY720 given at 30 days post clone 13 infection also induced complete clearance of virus. In both experiments, clearance was completely dependent upon CD4 cells, demonstrating that the drug is not acting directly on virus. These discoveries raise a number of important questions that are being studied in this grant: exploration of mechanisms through which FTY720 is promoting clearance of LCMV; determining whether FTY720 also induces reversal of LCMV-induced generalized immunosuppression; asking whether FTY720 also improves immune responses to other viral infections. Treatment with FTY720, which acts on host-immune cells and has no direct specific antiviral effects, might prove useful in treating chronic viral infections in humans, such as HIV, HBV, or HCV.