PERSISTENT VIRUS ON CENTRAL NERVOUS SYSTEM IMMUNITY

描述(摘自申请人摘要)：人类免疫缺陷病毒-1(HIV) 在急性疾病期间感染中枢神经系统。然而，缺乏一个有效的 灭菌免疫导致持续性中枢神经系统感染，这可能是 与艾滋病和痴呆症(ADC)的进展有关。CD8+T细胞是 似乎控制急性和慢性的关键免疫效应器 感染。然而，在病毒最初减少后，CD8+T细胞 在脑脊液中发现，也与脑脊液特有的病变有关 艾滋病脑炎。CD8+T细胞不能提供中枢神经系统局部不育 人们对免疫及其致病潜力知之甚少。这 建议研究CD8+T细胞在独特的免疫学中的调节 中枢神经系统的环境。目标1检验的假设是CD8+T细胞 急性感染缓解后滞留在中枢神经系统内的驱动因素 残留的病毒抗原。如果我们的假设是正确的，只有CD8+T细胞对 持久的表位将持久地保留在中枢神经系统内。目标2 验证CD8+T细胞被招募到HIV+CNS的假设 来自一个还没有达到完全记忆表型的池。如果我们的 假设是正确的，记忆细胞将有效地清除Ag，但 即使在CNS抗原表达缺失后，仍能继续表达细胞溶解活性。 这可能表明存在于HIV+CNS中的CD8+T细胞来源于 幼稚的前体，在进入CNS后可能在功能上下调，原因是 继续激活。Aim 3检验假设CNS保留CD8+T细胞 细胞不仅在表达溶细胞活性方面存在缺陷，而且 在增殖方面有缺陷。这些数据将决定CD8+T细胞 保留在Ag+CNS中的是停滞不前的，这为 缺乏细胞溶解活性和病毒清除。AIM 4解决四个问题 抗原驱动的中枢神经系统对CD8+T细胞的募集 外周：1)CNS Ag促进活化的CD8+T细胞募集；2) 抗原加局灶性炎症是否影响活化的CD8+T细胞的募集 细胞；3)CNS Ag是否影响记忆CD8+T细胞的募集；4)是 中枢神经系统抗原相关时记忆CD8+T细胞募集增加 局灶性炎症。接受者包括持续感染的小鼠(带有 不同类型的残余炎症)和转基因模型中的Ag 仅在任一星形胶质细胞、仅实质小胶质细胞、有限的 外周血粒单核细胞(包括血管周围小胶质细胞)数量 星形胶质细胞和外周血粒单核细胞均有表达。考虑到混合的 HIV+患者外周血L CD8+T细胞表型的研究 确定持续的Ag和/或局灶性炎症对特定的 招募CD8+T细胞亚群。我们的假设是最近激活的 CD8+T细胞优先被与炎症相关的抗原招募， 从而有助于病毒的持续存在。转基因小鼠的使用将 确定在已定义的CNS细胞类型中表达的Ag在 有无外周抗原。

DESCRIPTION (from applicant's abstract): Human immunodeficiency virus-1 (HIV) infects the CNS during acute disease. However, the absence of an effective sterilizing immunity results in persistent CNS infection which may contribute to the progression of AIDS and the dementia complex (ADC). CD8+ T cells are the critical immune effectors which appear to control both acute and chronic infection. However, following the initial reduction in virus, CD8+ T cells are found within the CSF and are also associated with the lesions characteristic of AIDS encephalitis. The inability of CD8+ T cells to provide local CNS sterile immunity as well as their pathogenic potential are poorly understood. This proposal examines CD8+ T cell regulation within the unique immunological environment of the CNS. Aim 1 examines the hypothesis is that CD8+ T cell retention within the CNS following resolution of acute infection is driven by residual viral Ag. If our hypothesis is correct, only CD8+ T cells reactive to the persistent epitope will be persistently retained within the CNS. Aim 2 tests the hypothesis that CD8+ T cells recruited into the HIV+ CNS are derived from a pool that has not achieved a complete memory phenotype. If our hypothesis is correct, memory cells will be effective in clearing Ag, but will continue to express cytolytic activity even after CNS Ag expression is lost. This would suggest that the CD8+ T cells present in the HIV+ CNS, derived from naive precursors, may be functionally downregulated after CNS entry due to continued activation. Aim 3 tests the hypothesis is that CNS retained CD8+ T cells are not only defective in expression of cytolytic activity, are also defective in proliferation. These data will determine if the CD8+ T cells retained within the Ag+ CNS are in stasis providing a possible explanation for the absence of cytolytic activity and viral clearance. Aim 4 addresses four issues relative to Ag driven CNS recruitment of CD8+ T cells from the periphery: 1) is recruitment of activated C D 8+ T cells enhanced by CNS Ag; 2) does Ag plus focal inflammation influence recruitment of activated CD8+ T cells; 3) does CNS Ag influence recruitment of memory C D 8+ T cells; and 4) is recruitment of memory C D 8+ T cells increased when CNS Ag is associated with focal inflammation. Recipients include persistently infected mice (with different types of residual inflammation) and transgenic models in which Ag is expressed in either astrocytes only, parenchymal microglia only, a limited number of peripheral myelomonocytic cells (including perivascular microglia) and both astrocytes and peripheral myelomonocytic cells. Given the mixed phenotypes of PB L C D 8+ T cells HIV+ patients, these experiments will determine persistent Ag and/or focal inflammation influences on specifically recruiting C D 8+ T cell subsets. Our hypothesis is that recently activated CD8+ T cells are preferentially recruited by Ag associated with inflammation, thereby contributing to viral persistence. The use of transgenic mice will determine the role of Ag expressed within defined CNS cell types, in the presence and absence of peripheral Ag.