PERSISTENT VIRUS ON CENTRAL NERVOUS SYSTEM IMMUNITY

描述（来自申请人摘要）：人类免疫缺陷病毒-1（HIV） 在急性期感染中枢神经系统。然而，缺乏有效的 绝育免疫导致持续的CNS感染， 艾滋病和痴呆综合症（ADC）的进展。CD 8 + T细胞是 关键的免疫效应物，其似乎控制急性和慢性 感染然而，在病毒的初始减少之后，CD 8 + T细胞被激活。 在CSF中发现，也与以下特征性病变相关： 艾滋病脑炎。CD 8 + T细胞不能提供局部CNS无菌 免疫及其致病潜力知之甚少。这 该提案研究了CD 8 + T细胞在独特的免疫调节中的调节作用。 CNS的环境。目的1验证CD 8 + T细胞 急性感染消退后CNS内的滞留由以下因素驱动： 残留病毒抗原如果我们的假设是正确的，只有CD 8 + T细胞对 持久表位将持久地保留在CNS内。目的2 检验了募集到HIV+ CNS中的CD 8 + T细胞来源于 从一个没有获得完整记忆表型的池中。如果我们的 假设是正确的，记忆细胞将有效清除Ag，但将 甚至在CNS Ag表达丧失后继续表达细胞溶解活性。 这表明HIV+ CNS中存在的CD 8 + T细胞，来源于 幼稚前体，可能是功能下调后，中枢神经系统进入，由于 继续激活。目的3检验CNS保留CD 8 + T细胞的假设， 细胞不仅在细胞溶解活性的表达方面存在缺陷，而且 在增殖中有缺陷。这些数据将确定CD 8 + T细胞是否 保留在Ag+ CNS内的细胞处于停滞状态，这为以下情况提供了可能的解释： 缺乏细胞溶解活性和病毒清除。目标4涉及四个方面 与Ag驱动的CD 8 + T细胞的CNS募集相关的问题 外周：1）是CNS Ag增强的活化CD 8+ T细胞的募集; 2） Ag+局灶性炎症是否影响活化的CD 8 + T细胞的募集 细胞; 3）CNS Ag是否影响记忆CD 8+ T细胞的募集;以及4） 当CNS Ag与CD 8+ T细胞的增殖相关时， 局部炎症。接受者包括持续感染的小鼠（具有 不同类型的残余炎症）和转基因模型，其中Ag被 仅在星形胶质细胞、仅在实质小胶质细胞、仅在星形胶质细胞、仅在实质小胶质细胞和仅在实质小胶质细胞中表达。 外周骨髓单核细胞数量（包括血管周围小胶质细胞） 以及星形胶质细胞和外周骨髓单核细胞。鉴于混合 PB L C D 8+ T细胞HIV+患者的表型，这些实验将 确定持续性Ag和/或局灶性炎症对特异性 募集CD 8+ T细胞亚群。我们的假设是最近激活的 CD 8 + T细胞优先被与炎症相关的Ag募集， 从而导致病毒持续存在。转基因小鼠的使用将 确定在确定的CNS细胞类型中表达的Ag的作用， 存在和不存在外周Ag。

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.