Reconstitution of Protective CMV Immunity and Immune Regulation After HAART

描述(由申请人提供)：免疫重建是高效抗逆转录病毒疗法(HAART)的一个关键目标，在接受HAART的HIV感染患者中，免疫重建是不完整的，表现为对疫苗的体液和细胞免疫反应不足，以及对包括巨细胞病毒(CMV)在内的疱疹病毒的免疫恢复不足。我们假设HIV感染的患者积累了过量的调节性T细胞(Treg)，这会损害免疫重建。这一假设将以HAART受者的CMV感染为模型进行验证。CMV是一个很好的模型，因为它提供了自然病毒学(病毒血症)和临床(终末期器官疾病) [EOD])终点分别出现在20%到38%和2%到20%的接受HAART的个体中。另一个临床终点是死亡，这与HAART受者的CMV病毒血症有关。本研究的目的是确定一个强大的免疫学标志物，以防止CMV病毒血症、EOD和死亡，然后确定Treg在HAART受者未能重建CMV保护性免疫应答中的作用。这项研究将使用冷冻保存的外周血单核细胞(PBMC)和艾滋病临床试验小组储存的血浆进行。在发展病毒学或临床终点之前获得的PBMC上，将使用基于ELISPOT、EL ISA和流式细胞术的检测CMV特异性的CD4+和CD8+功能和数量的分析来评估CMV的免疫力。统计分析将确定预防CMV病毒血症、EOD和死亡的两个最强大的免疫相关因素。这两个免疫参数将在CMV病毒血症发作后收集的PBMC上进行测量，以识别具有和不具有CMV特异性免疫重建的受试者。通过表型和细胞因子的产生来评估自然和CMV诱导的Treg活性，将与CMV病毒血症、EOD和死亡的发生以及CMV保护性免疫功能在统计学上相关。经统计证实的Treg与CMV免疫功能缺陷的相关性将通过体外细胞/细胞因子耗尽/重建实验得到证实。这些分析将确定Treg在HAART受者CMV免疫重建不足中的作用。

DESCRIPTION (provided by applicant): Immune reconstitution, a crucial goal of highly active antiretroviral therapy (HAART), is incomplete in HIV infected patients on HAART as demonstrated by inadequate humoral and cell-mediated immune responses to vaccines and deficient recovery of immunity against herpesviruses including cytomegalovirus (CMV). We hypothesize that HIV-infected patients accumulate an excess of regulatory T cells (Treg) that impair immune reconstitution. This hypothesis will be tested using CMV infection in HAART recipients as a model. CMV constitutes an excellent model because it provides natural virologic (viremia) and clinical (end organ disease [EOD]) end points that occur in 20 to 38% and 2 to 20%, respectively, of individuals on HAART. An additional clinical end point is death, which has been associated with CMV viremia in HAART recipients. The aims of this study are to identify a robust immunologic marker of protection against CMV viremia, EOD and death and then to determine the role of TREG in the failure of HAART recipients to reconstitute CMV-protective immune responses. The study will be conducted using cryopreserved peripheral blood mononuclear cells (PBMC) and plasma stored by the AIDS Clinical Trials Group. CMV immunity will be assessed on PBMC obtained before development of virologic or clinical end points using ELISPOT-, ELISA- and flow cytometry-based assays that measure CMV-specific CD4+ and CD8+ function and numbers. Statistical analyses will identify the 2 most robust immune correlates of protection against CMV viremia, EOD and death. These 2 immune parameters will be measured on PBMC collected after =1 episode of CMV viremia to identify subjects with and without CMV-specific immune reconstitution. The natural and CMV-induced TREG activity, assessed phenotypically and by cytokine production, will be statistically correlated with development of CMV viremia, EOD and death and with CMV protective immune functions. Statistically identified correlations of TREG with deficits of CMV immune functions will be confirmed by ex vivo cell/cytokine depletion/reconstitution experiments. These analyses will define the role of TREG in the inadequate CMV immune reconstitution of HAART recipients.