Analysis of FOXP3+ regulatory T cells that display apparent viral antigen specificity during chronic hepatitis C virus infection.

We reported previously that a proportion of natural CD25(+) cells isolated from the PBMC of HCV patients can further upregulate CD25 expression in response to HCV peptide stimulation in vitro, and proposed that virus-specific regulatory T cells (Treg) were primed and expanded during the disease. Here we describe epigenetic analysis of the FOXP3 locus in HCV-responsive natural CD25(+) cells and show that these cells are not activated conventional T cells expressing FOXP3, but hard-wired Treg with a stable FOXP3 phenotype and function. Of approximately 46,000 genes analyzed in genome wide transcription profiling, about 1% were differentially expressed between HCV-responsive Treg, HCV-non-responsive natural CD25(+) cells and conventional T cells. Expression profiles, including cell death, activation, proliferation and transcriptional regulation, suggest a survival advantage of HCV-responsive Treg over the other cell populations. Since no Treg-specific activation marker is known, we tested 97 NS3-derived peptides for their ability to elicit CD25 response (assuming it is a surrogate marker), accompanied by high resolution HLA typing of the patients. Some reactive peptides overlapped with previously described effector T cell epitopes. Our data offers new insights into HCV immune evasion and tolerance, and highlights the non-self specific nature of Treg during infection.

Apoptosis induced in synchronized human immunodeficiency virus type 1-infected primary peripheral blood mononuclear cells is detected after the peak of CD4+ T-lymphocyte loss and is dependent on the tropism of the gp120 envelope glycoprotein.

Disease progression in human immunodeficiency virus type-1 (HIV-1)-infected individuals is frequently accompanied by declining CD4 cell numbers and the acquisition of a T-tropic (X4) or dual tropic (R5X4) phenotype. Understanding the mechanism of CD4 cell loss in HIV-1 infection is essential for the development of effective therapeutic strategies. In this study, donor populations of peripheral blood mononuclear cells (PBMCs) were selected for their ability to support an equivalent acute infection by both R5 and X4 virus phenotypes. This demonstrated that CD4+ T-lymphocyte loss was due to the gp120 region of Env and was replication independent. Furthermore, apoptosis was only detected in cells infected with an X4 virus after the majority of CD4+ T-lymphocyte loss had occurred. These observations indicate that the CD4+ T-lymphocyte loss in an X4 HIV-1 infection is not directly mediated by apoptosis, although apoptosis may be induced in the remaining cell population as a consequence of this CD4+ T-lymphocyte loss.