Reconstitution of Protective CMV Immunity and Immune Regulation After HAART

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，免疫重建是不完整的，这表现为对疫苗的体液和细胞介导的免疫反应不足，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感染患者积累了过量的调节性T细胞（Treg），损害了免疫重建。这一假设将以HAART受者的巨细胞病毒感染为模型进行检验。巨细胞病毒是一个很好的模型，因为它提供了自然病毒学（病毒血症）和临床（终末器官疾病）

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.