Regulatory T Cells and the Risk of CMV End-Organ Disease in Patients With AIDS

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Abstract
Objectives: Cytomegalovirus (CMV)-specific T-cell effectors (CMV-Teff) protect against CMV end-organ disease (EOD). In HIV-infected individuals, their numbers and function vary with CD4+ cell numbers and HIV load. The role of regulatory T cells (Treg) in CMV-EOD has not been extensively studied. We investigated the contribution of Treg and Teff toward CMV-EOD in HIV-infected individuals independently of CD4+ cell numbers and HIV load and controlling for CMV reactivations. Design: We matched 43 CMV-EOD cases to 93 controls without CMV-EOD, but with similar CD4+ cell numbers and HIV plasma RNA. CMV reactivation was investigated by blood DNA polymerase chain reaction over 32 weeks preceding the CMV-EOD in cases and preceding the matching point in controls. Methods: CMV-Teff and Treg were characterized by the expression of interferon-γ (IFN-γ), interleukin 2, tumor necrosis factor α (TNFα), MIP1β, granzyme B (GrB), CD107a, TNFα, FOXP3, and CD25. Results: Sixty-five percent cases and 20% controls had CMV reactivations. In multivariate analyses that controlled for CMV reactivations, none of the CMV-Teff subsets correlated with protection, but high CMV-GrB enzyme-linked immunosorbent spot responses and CMV-specific CD4+FOXP3+%, CD4+TNFα+%, and CD8+CD107a+% were significant predictors of CMV-EOD. Conclusions: Because both FOXP3 and GrB have been previously associated with Treg activity, we conclude that CMV-Treg may play an important role in the development of CMV-EOD in advanced HIV disease. We were not able to identify a CMV-Teff subset that could be used as a surrogate of protection against CMV-EOD in this highly immunocompromised population.

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