Role of antibodies in a primarily T cell-controlled viral infection model in mice

对非致细胞病变病毒如人类丙型肝炎病毒（HCV）或小鼠淋巴细胞性脉络膜脑膜炎病毒（LCMV）的控制主要由CD8 T细胞介导。体液免疫被认为是次要的，因为中和抗体出现较晚且滴度较低。在我们初步的项目特定工作中，我们分析了抗体形成受损的小鼠，并惊讶地发现，与清除感染的野生型小鼠相比，用快速复制的LCMV毒株进行低剂量感染会导致T细胞耗竭和病毒持久性。因此，在感染后的早期时间点存在的天然或诱导的LCMV特异性抗体可以降低病毒复制并有助于T细胞介导的清除，尽管缺乏中和活性。该项目的总体目标是为这一假设提供直接证据，并阐明非中和LCMV特异性抗体如何降低病毒载量和防止T细胞耗竭的机制。工作计划包括将抗体和B细胞过继转移至抗体缺陷型受体小鼠，然后进行LCMV感染，随后检查病毒清除和T细胞活性。此外，将生成一组携带不同同种型的LCMV特异性单克隆抗体，并确定其作用方式。

Control of non-cytopathic viruses such as hepatitis C virus (HCV) in humans or lymphocytic choriomenigitis virus (LCMV) in mice is primarily mediated by CD8 T cells. Humoral immunity is considered to be of minor importance since neutralizing antibodies appear only late and are of low titer. In our preliminary project-specific work, we analyzed mice with impaired antibody formation and surprisingly found that low dose infection with a rapidly replicating LCMV strain led to T cell exhaustion and virus persistence in contrast to wild-type mice that cleared the infection. Thus, natural or induced LCMV-specific antibodies present at early time points after infection may lower viral replication and assist in T cell-mediated clearance despite lack of neutralization activity. The overall aim of this project is to provide direct evidence for this hypothesis and to clarify the mechanisms of how non-neutralizing LCMV-specific antibodies decrease viral load and prevent T cell exhaustion. The work schedule involves adoptive transfer experiments with antibodies and B cells into antibody-deficient recipient mice followed by LCMV infection and subsequent examination of viral clearance and T cell activity. In addition, a panel of LCMV-specific monoclonal antibodies carrying different isotypes will be generated and their mode of action will be determined.