The APPEESFRS Peptide, Restricted by the HLA-B*35:01 Molecule, and the APPEESFRF Variant Derived from an Autologous HIV-1 Strain Induces Polyfunctional Responses in CD8+ T Cells.

Liliana Acevedo-Sáenz,Julio C Delgado,María Teresa Rugeles L,Liseth Carmona-Pérez,Paula Andrea Velilla-Hernández

doi:10.1089/biores.2014.0054

Abstract

Numerous reports have focused on consensus peptides to determine CD8+ T-cell responses; however, few studies evaluated the functional profile using peptides derived from circulating strains of a specific region. We determined the effector profile and maturation phenotype of CD8+ T-cells targeting the consensus APPEESFRS (AS9) epitope and its variant APPEESFRF (AF9), previously identified. The free energy of binding, maturation phenotype, and polyfunctional profile of both peptides were similar. The magnitude of CD8+ T-cell responses to AF9 was greater than the one elicited by AS9, although the difference was not significant. The polyfunctional profile of AF9 was characterized by CD107a/interleukin-2 (IL-2)/macrophage inflammatory protein beta (MIP1β) and by interferon gamma (IFNγ)/MIP1β/tumor necrosis factor alpha (TNFα) in response to AS9. TNFα production was significantly higher in response to AF9 than to AS9, and there was a negative correlation between the absolute number of CD8+ T-cell-producing TNFα and the plasma human immunodeficiency virus (HIV) load, suggesting a role of this cytokine in the control of HIV replication.

Highlights

CD8 + T cells play an important role in the control of human immunodeficiency virus (HIV) replication, both in the acute and chronic phases of infection.[1,2]Several studies have focused on the identification of immunodominant epitopes of CD8 + T cells, capable of inducing strong specific responses;[3] such studies have been hampered by the high genetic variability of the virus.[4,5] Given this genetic heterogeneity, the evaluation of HIV-specific CD8 + T cells is frequently performed using consensus peptides derived from viral sequences belonging to the M group[6] of HIV-1
This approach is practical, has cost–benefit advantages, and has generated a large amount of information; few studies have focused on the evaluation of the functional profile of HIV-specific CD8 + T cells in response to peptides derived from circulating strains of a specific region that may vary between strains of the same HIV subtype.[7]
Taking into consideration that a single amino acid change in the peptide could affect/eliminate the binding to the major histocompatibility complex (MHC) molecule, reducing the recognition of the peptide by the T cell receptor or inducing an inefficient CD8 + T cell response,[9,10,11] our objective was to evaluate the influence of the S465F mutation in the APPEESFRS peptide on the functional profile of HLA-B*35:01-restricted CD8 + T cells, in Colombian HIV-1 chronically infected patients

Summary

Introduction

CD8 + T cells play an important role in the control of human immunodeficiency virus (HIV) replication, both in the acute and chronic phases of infection.[1,2]. Several studies have focused on the identification of immunodominant epitopes of CD8 + T cells, capable of inducing strong specific responses;[3] such studies have been hampered by the high genetic variability of the virus.[4,5] Given this genetic heterogeneity, the evaluation of HIV-specific CD8 + T cells is frequently performed using consensus peptides derived from viral sequences belonging to the M group[6] of HIV-1 This approach is practical, has cost–benefit advantages, and has generated a large amount of information; few studies have focused on the evaluation of the functional profile of HIV-specific CD8 + T cells in response to peptides derived from circulating strains of a specific region (autologous peptides) that may vary between strains of the same HIV subtype.[7] A study of Doroudchi et al reported that a greater magnitude of CD8 + T cells expressing interferon gamma (IFNc) was observed when the cells were stimulated with autologous instead of consensus HIV-1 peptides derived from the Nef protein, underlying the importance of using circulating strains to define immunogenic peptides with immunotherapy potential.[8].

Objectives

Methods

Results

Conclusion