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Reconstitution of Protective CMV Immunity and Immune Regulation After HAART

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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.

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