Gene expression signatures of peripheral CD4+ T cells clearly discriminate between patients with acute and chronic hepatitis B infection

Abstract

CD4+ T and regulatory T cells (Tregs) seem to play a key role in persistence of hepatitis B virus (HBV) infection. However, the molecular events by which Tregs exert their modulatory activity are largely unknown. The transcriptional profiles of CD4+ T cells of healthy controls (HCs) and patients affected by acute hepatitis B (AVH‐B) or chronic hepatitis B (CHB) infection were established using a custom expression array consisting of 350 genes relevant for CD4+ T cell and Treg function. These studies were complemented by real‐time reverse‐transcription polymerase chain reaction. Peripheral blood mononuclear cells (PBMCs) were also analyzed for the presence of Tregs, which were more abundant in the acute stage of the disease (7%) than in HCs and CHB infection (HCs versus AVH‐B, P = 0.003; AVH‐B versus CHB, P = 0.04). One hundred eighteen genes (34%) intrinsically differentiate HBV‐infected patients from HCs. Using gene ontology, we identified T cell receptor signaling and clusterization, mitogen‐activated protein kinase kinase signaling, cell adhesion, cytokines and inflammatory responses, cell cycle/cell proliferation, and apoptosis as the most prominent affected modules. A higher expression of CCR1, CCR3, CCR4, CCR5, and CCR8 was seen in AVH‐B than in CHB‐infected patients and HCs. Annotation of the interconnected functional network of genes provided a unique representation of global immune activation during acute infection. Almost all genes were down‐regulated in patients with CHB infection. Conclusion: The fingerprints enable clear discrimination between patients suffering from AVH‐B or CHB infection. The observed profiles suggest accumulation of effector T cells with a potential role in necro‐inflammation during the acute stage. Subsequent down‐regulated effector functions support the hypothesis of suppressed CD4+ effector T cells favoring viral persistence in the chronic infection stage. (HEPATOLOGY 2009.)