The Th17/Treg Ratio, IL-1RA and sCD14 Levels in Primary HIV Infection Predict the T-cell Activation Set Point in the Absence of Systemic Microbial Translocation

Laurence Weiss,Gaël Petitjean,Mathieu F. Chevalier,Daniel Scott-Algara,Maria Elena Manea,Christine Rouzioux,Laurence Meyer,Pierre-Marie Girard,Françoise Barré-Sinoussi,Céline Didier,Catherine Dunyach-Rémy,Jean-Philippe Lavigne,Pauline Campa

doi:10.1371/journal.ppat.1003453

Abstract

Impairment of the intestinal barrier and subsequent microbial translocation (MT) may be involved in chronic immune activation, which plays a central role in HIV pathogenesis. Th17 cells are critical to prevent MT. The aim of the study was to investigate, in patients with primary HIV infection (PHI), the early relationship between the Th17/Treg ratio, monocyte activation and MT and their impact on the T-cell activation set point, which is known to predict disease progression. 27 patients with early PHI were included in a prospective longitudinal study and followed-up for 6 months. At baseline, the Th17/Treg ratio strongly negatively correlated with the proportion of activated CD8 T cells expressing CD38/HLA-DR or Ki-67. Also, the Th17/Treg ratio was negatively related to viral load and plasma levels of sCD14 and IL-1RA, two markers of monocyte activation. In untreated patients, the Th17/Treg ratio at baseline negatively correlated with CD8 T-cell activation at month 6 defining the T-cell activation set point (% HLA-DR+CD38+ and %Ki-67+). Soluble CD14 and IL-1RA plasma levels also predicted the T-cell activation set point. Levels of I-FABP, a marker of mucosal damages, were similar to healthy controls at baseline but increased at month 6. No decrease in anti-endotoxin core antibody (EndoCAb) and no peptidoglycan were detected during PHI. In addition, 16S rDNA was only detected at low levels in 2 out 27 patients at baseline and in one additional patient at M6. Altogether, data support the hypothesis that T-cell and monocyte activation in PHI are not primarily driven by systemic MT but rather by viral replication. Moreover, the “innate immune set point” defined by the early levels of sCD14 and IL-1RA might be powerful early surrogate markers for disease progression and should be considered for use in clinical practice.

Highlights

High levels of immune activation occur early in primary HIV infection (PHI) and the CD8 T-cell activation set point is a strong predictor of subsequent CD4 T-cell loss independently of viral load [1]
The Th17/Treg ratio was negatively related to viral load and plasma levels of sCD14 and IL-1 receptor antagonist (IL-1RA), two markers of monocyte activation
Th17 cells are involved in epithelial barrier integrity and a loss of the balance between Th17 and regulatory T cells (Tregs) has been associated with disease progression

Summary

Introduction

High levels of immune activation occur early in primary HIV infection (PHI) and the CD8 T-cell activation set point (i.e. the steady state level of activation following PHI) is a strong predictor of subsequent CD4 T-cell loss independently of viral load [1]. Impairment of the intestinal barrier and subsequent microbial translocation might be one of the main causes of chronic T-cell activation [5], together with innate and adaptive immune responses, stimulation by HIV viral proteins and reactivation of other viruses (e.g. cytomegalovirus, hepatitis viruses) (reviewed in Appay and Sauce [6]). LPS levels were shown to be elevated in chronic HIV infection – but not significantly during PHI – and to correlate with T-cell activation [9]. In viremic chronic HIV-infected patients, the spontaneous production of IL-1 by circulating monocytes suggested that these cells were activated in vivo [10]. SCD14 levels were shown to predict mortality in chronically HIV-infected patients [12] as well as in other contexts

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