CD4 T-Cell Responses in Primary HIV Infection: Interrelationship with Immune Activation and Virus Burden

Mathieu F Chevalier,Pauline Campa,Maria E Manea,Françoise Barré-Sinoussi,Pierre-Marie Girard,Laurence Weiss,Daniel Scott-Algara,Céline Didier

doi:10.3389/fimmu.2016.00395

Abstract

Early events during primary HIV infection (PHI) are thought to influence disease outcome. Although a growing body of evidence suggests a beneficial role of HIV-specific CD4 help in HIV infection, it is unclear how early viral replication, systemic immune activation, and antiretroviral therapy (ART) may shape CD4 T-cell responses during PHI, and whether HIV-specific CD4 responses contribute to the high immune activation observed in PHI. Twenty-seven patients with early PHI were included in a prospective longitudinal study and 12 of them received ART after enrollment. Fresh peripheral blood mononuclear cells were used for measurement of ex vivo T-cell activation and of cytokine-producing CD4 T-cells following stimulation with PMA/ionomycin or HIV-1-gag-p24 antigen. Patients were segregated based on CD8 T-cell activation level (i.e., % HLA-DR+CD38+ CD8 T-cells) at baseline (BL). Patients with lower immune activation exhibited higher frequency of bulk CD4 T-cells producing IFN-γ or IL-17 and higher effector-to-regulatory cell ratios. No differences were found in HIV-specific CD4 T-cell frequencies. In contrast, segregation of patients based on plasma viral load (pVL) revealed that patients with higher pVL showed higher cytokine-producing HIV-specific CD4 responses. Of note, the frequency of IFN-γ+ HIV-specific CD4 T cells significantly diminished between BL and month 6 only in ART-treated patients. However, early treatment initiation was associated with better maintenance of HIV-specific IFN-γ+ CD4 T-cells. These data suggest that HIV-specific CD4 responses do not fuel systemic T-cell activation and are driven by viral replication but not able to contribute to its control in the early phase of infection. Moreover, our data also suggest a benefit of early treatment for the maintenance of HIV-specific CD4 T-cell help.

Highlights

CD4 T helper cells are crucial to orchestrate immune responses to viral infections by recruiting key immune cells into tissues, by providing help for expansion and function of B cells and CD8 T cells, and by direct cell-mediated cytotoxicity [1]
We showed that a high immune activation level in primary HIV infection (PHI) was associated with lower polyclonal IFN-γ+ and IL-17+ T-cell responses, while no association was found with HIV-specific T-cell frequencies
ARTmediated viral control was associated with a decrease in IFN-γproducing HIV-specific CD4 T cells from BL to month 6 of follow-up (M6), the earlier antiretroviral therapy (ART) was introduced, the higher was the residual IFN-γ+ HIV-specific CD4 responses

Summary

Introduction

CD4 T helper cells are crucial to orchestrate immune responses to viral infections by recruiting key immune cells into tissues, by providing help for expansion and function of B cells and CD8 T cells, and by direct cell-mediated cytotoxicity [1]. Several studies ascribed a protective role to HIV-specific CD4 T cells with regard to viremia and disease progression [3,4,5,6,7], as well as in vaccine-mediated protection against HIV acquisition [8, 9]. T helper responses during primary HIV infection (PHI) may be of particular interest as early events are thought to influence disease outcome. HIV-specific proliferative CD4 T-cell responses are quite limited in most patients during PHI [10], cytokine-producing virusspecific CD4 T cells have been clearly identified during PHI in several recent studies [4, 11,12,13]. HIV-specific CD4 and CD8 T cells arise with distinct kinetics during PHI, with specific CD4 T cells reaching their maximal frequency within few weeks post-infection, while CD8 T cells gradually increase for several months [11]

Methods

Results

Conclusion