Immune Regulation of CNS Viral Recrudescence

描述（由申请人提供）：多种人类病毒，包括 疱疹病毒、B型肝炎病毒和HIV引起急性感染， 持续或复发。然而，调节持久性的机制 和复发取决于病毒复制和宿主之间的平衡 免疫反应病毒嗜性和抗原载量提供了额外的 在这个复杂的系统中。本提案审查了以下方面的贡献： 细胞免疫和体液免疫在控制复发中的作用 嗜神经性病毒，初始清除后。免疫活性细胞感染 小鼠诱导急性脑脊髓炎，随后持续存在， 传染性病毒在急性感染期间，细胞介导的免疫，主要是 CD 8 + T细胞，在控制病毒复制中至关重要。 中枢神经系统（CNS）。然而，在缺乏B细胞的情况下，这些 效应子功能不足以将病毒抑制到不可检测的水平， 从而允许病毒再活化。重要的是，抗病毒药物的转移 抗体（Ab）可防止病毒再活化，这表明Ab 和/或B细胞在控制持久性中的作用。然而，病毒特异性分析 使用I类tetramet技术的T细胞显示， 与免疫活性小鼠相比，CNS中的特异性CD 8 + T细胞减少。 此外，在治疗期间，病毒特异性T细胞没有增加。 重新激活这些数据表明，CD 8 + T细胞可能在功能上是 由于抗原负荷增加而受损或耗尽。这项建议 区分强效CD 8 + T细胞功能与Ab 控制病毒在持续感染的宿主中重新激活。的 中和和非中和Ab、Fc受体（FcR）的贡献 活性和补体通过Ab转移和使用缺陷型小鼠来检查 在FeR。这些实验将确定Ab介导的 在Ab缺乏的环境中防止病毒再活化。的可能性 Ab和/或B细胞的缺乏导致缺陷性CD 8 + T细胞引发， 最终导致复发期间的衰竭， 以及在引发和复发期间的CD 8 + T细胞的表型分析。 通过转移体外活化的保护性Ab或CD 8 + T细胞进行干预 将确定是否可以克服功能受损的CD 8 + T细胞。这些 实验可能对治疗干预有直接影响， 持续性病毒感染。最后，病毒再激活将在 具有正常B细胞区室的Ab缺陷小鼠。这些实验将 区分B细胞的Ab独立效应的可能性 以及与B细胞缺乏相关的CD 8 + T细胞缺陷。这项建议会 提供了深入了解免疫调节病毒复发， 而中枢神经系统作为靶器官。

DESCRIPTION (provided by applicant): A variety of human viruses, including herpes viruses, hepatitis B virus and HIV, produce acute infections followed by persistence or recrudescence. However, the mechanism(s) regulating persistence and recrudescence depend on a balance between viral replication and the host immune response. Viral tropism and antigenic load provide additional determinants in this complex scheme. This proposal examines the contribution of cell mediated and humoral immunity in controlling recrudescence of a neurotropic virus following initial clearance. Infection of immunocompetent mice induces an acute encephalomyelitis, followed by persistence without infectious virus. During acute infection cell mediated immunity, predominantly the CD8+ T cells, are crucial in controlling virus replication within the central nervous system (CNS). However, in the absence of B cells, these effector functions do not suffice to suppress virus to undetectable levels, thereby allowing virus reactivation. Importantly, transfer of anti-viral antibody (Ab) prevents virus reactivation, implicating a crucial role for Ab and/or B cells in controlling persistence. However, analysis of virus specific T cells using class I tetramet technology revealed that the percentage of virus specific CD8+ T cells in the CNS is reduced compared to immunocompetent mice. In addition, there is no increase in virus specific T cells during reactivation. These data suggested that CD8+ T cells may be functionally impaired or exhausted due to increased antigen load. This proposal distinguishes between the requirement(s) for potent CD8+ T cell function vs Ab in controlling virus reactivation in a persistently infected host. The contribution of both neutralizing and non neutralizing Ab, Fc receptor (FcR) activity and complement are examined by Ab transfers and using mice deficient in FeR. These experiments will determine the mechanism of Ab mediated prevention of virus reactivation in an Ab deficient milieu. The possibility that the absence of Ab and/or B cells results in defective CD8+ T cell priming, ultimately leading to exhaustion during recrudescence is tested by functional and phenotypic analysis of CD8+ T cells during priming and recrudescence. Intervention via transfer of protective Ab or CD8+ T cells activated in vitro will determine if functionally impaired CD8+ T cells can be overcome. These experiments may have direct implications for therapeutic interventions during persistent viral infections. Finally, virus reactivation will be tested in an Ab deficient mouse with a normal B cell compartment. These experiments will distinguish between the possibilities of an Ab independent effect of B cells and a CD8+ T cell defect related to the absence of B cells. This proposal will provide insight into the immunological regulation of both virus recrudescence and the CNS as a target organ.