Reconstitution of Protective CMV Immunity and Immune Regulation After HAART

描述（由申请方提供）：免疫重建是高效抗逆转录病毒治疗（HAART）的一个关键目标，但在接受HAART治疗的HIV感染患者中不完全，表现为对疫苗的体液和细胞介导的免疫应答不足，以及对疱疹病毒（包括巨细胞病毒（CMV））的免疫力恢复不足。我们假设HIV感染患者积累了过量的调节性T细胞（Treg），从而损害免疫重建。将使用HAART接受者中的CMV感染作为模型来检验这一假设。CMV是一个很好的模型，因为它提供了自然的病毒学（病毒血症）和临床（终末器官疾病 [EOD]）分别发生在HAART个体的20 - 38%和2 - 20%中的终点。另一个临床终点是死亡，这与HAART接受者的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的保护，防止CMV病毒血症，EOD和死亡，然后确定的作用，TREG在失败的HAART收件人重建CMV保护性免疫反应。本研究将使用AIDS临床试验组储存的冻存外周血单核细胞（PBMC）和血浆进行。将使用基于ELISPOT、ELISA和流式细胞术的测定（测量CMV特异性CD 4+和CD 8+功能和数量），在病毒学或临床终点出现前获得的PBMC上评估CMV免疫力。统计学分析将鉴定针对CMV病毒血症、EOD和死亡的保护的2种最稳健的免疫相关性。将在≥ 1次CMV病毒血症发作后采集的PBMC上测量这2个免疫参数，以识别是否存在CMV特异性免疫重建的受试者。通过表型和细胞因子产生评估的天然和CMV诱导的TREG活性将与CMV病毒血症、EOD和死亡的发展以及CMV保护性免疫功能统计学相关。将通过离体细胞/细胞因子耗竭/重建实验证实统计学鉴定的TREG与CMV免疫功能缺陷的相关性。这些分析将确定TREG在HAART接受者的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.