Immune Regulation of CNS Viral Recrudescence

描述(申请人提供)：多种人类病毒，包括 疱疹病毒、乙肝病毒和艾滋病毒会引起急性感染，其次是 顽固或复发。然而，调节坚持的机制(S) 而复发取决于病毒复制和宿主之间的平衡 免疫反应。病毒嗜性和抗原负荷量提供了额外的 在这个复杂的计划中的决定因素。这份提案考察了 细胞免疫和体液免疫在控制黑色素瘤复发中的作用 最初清除后的嗜神经性病毒。免疫活性感染 小鼠诱发急性脑脊髓炎，随后没有持续 传染性病毒。在急性感染期间，主要是细胞免疫 CD8+T细胞对控制病毒在体内的复制至关重要 中枢神经系统(CNS)。然而，在没有B细胞的情况下，这些 效应器功能不足以将病毒抑制到无法检测的水平， 从而允许病毒重新激活。重要的是，抗病毒药物的转移 抗体(Ab)防止病毒重新激活，这意味着Ab起着至关重要的作用 和/或B细胞控制持久性。然而，对病毒特异性的分析 使用I类四聚体技术的T细胞显示病毒的百分比 与具有免疫能力的小鼠相比，中枢神经系统中的特异性CD8+T细胞减少。 此外，在治疗过程中，病毒特异性T细胞没有增加 重新激活。这些数据提示CD8+T细胞可能在功能上 由于抗原负荷增加而受损或精疲力竭。这项建议 区分(S)对强大的CD8+T细胞功能的要求与抗体 在持续感染的宿主中控制病毒的重新激活。这个 中和和非中和抗体Fc受体(FCR)的作用 通过抗体转移和使用缺陷小鼠来检测活性和补体 在FER里。这些实验将确定抗体介导的机制 在抗体缺乏的环境中防止病毒重新激活。这种可能性 缺乏抗体和/或B细胞会导致CD8+T细胞启动有缺陷， 最终导致复发期间的疲惫是由功能测试 CD8+T细胞在初发和复发过程中的表型分析。 通过转移体外激活的保护性抗体或CD8+T细胞进行干预 将决定功能受损的CD8+T细胞是否可以被克服。这些 实验可能对治疗干预有直接的影响 持续的病毒感染。最后，病毒重新激活将在一个 AB缺陷小鼠，B细胞室正常。这些实验将 区分B细胞抗体非依赖性效应的可能性 与B细胞缺失有关的CD8+T细胞缺陷。这项提议将 洞察两种病毒复发的免疫调节 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.