HIV infection of human regulatory T cells downregulates Foxp3 expression by increasing DNMT3b levels and DNA methylation in the FOXP3 gene

Abstract

Objective: Regulatory T cells (Tregs) play an important role in infections modulating host immune responses and avoiding overreactive immunity. The mechanisms underlying their action in HIV-infected patients have not been well established. HIV can infect Treg, but little is known about the effects of the infection on Treg phenotype and function. The objective of this study was to investigate whether in-vitro HIV infection modifies the phenotype and suppressive capacity of Treg cells.

Design: Because Treg cells are a subset of CD4 T cells, HIV infection could produce alterations in the phenotype and methylation pattern of Treg disturbing the functionality of these cells.

Methods: Isolated Treg cells from healthy volunteers were cultured in the presence of HIV-1, and phenotype, methylation pattern of FOXP3 locus, cytokine secretion profile and suppressive function of infected Treg were analysed in comparison with noninfected Treg.

Results: We demonstrate that HIV-1 directly infects Treg and deregulates the function and the phenotype that define these cells. HIV infection downregulates the Foxp3 expression in Treg, which is followed by the loss of suppressive capacity and alterations in cytokine secretion pattern, with decreased production of transforming growth factor-beta (TGF-β) and an increased production of interleukin (IL)-4. Foxp3 downregulation in HIV-infected Treg was related to an increase in the expression of DNA methyltransferase3b (DNMT3b) associated with higher methylation of CpG sites in the FOXP3 locus.

Conclusion: These findings are pivotal to our understanding of the role of Treg in HIV infection and indicate that regulatory function could be seriously impaired in HIV-infected patients contributing to the immune hyperactivation.