Early skewed distribution of total and HIV-specific CD8+ T-cell memory phenotypes during primary HIV infection is related to reduced antiviral activity and faster disease progression

PLoS One. 2014 Aug 5;9(8):e104235. doi: 10.1371/journal.pone.0104235. eCollection 2014.

Abstract

The important role of the CD8+ T-cells on HIV control is well established. However, correlates of immune protection remain elusive. Although the importance of CD8+ T-cell specificity and functionality in virus control has been underscored, further unraveling the link between CD8+ T-cell differentiation and viral control is needed. Here, an immunophenotypic analysis (in terms of memory markers and Programmed cell death 1 (PD-1) expression) of the CD8+ T-cell subset found in primary HIV infection (PHI) was performed. The aim was to seek for associations with functional properties of the CD8+ T-cell subsets, viral control and subsequent disease progression. Also, results were compared with samples from Chronics and Elite Controllers. It was found that normal maturation of total and HIV-specific CD8+ T-cells into memory subsets is skewed in PHI, but not at the dramatic level observed in Chronics. Within the HIV-specific compartment, this alteration was evidenced by an accumulation of effector memory CD8+ T (TEM) cells over fully differentiated terminal effector CD8+ T (TTE) cells. Furthermore, higher proportions of total and HIV-specific CD8+ TEM cells and higher HIV-specific TEM/(TEM+TTE) ratio correlated with markers of faster progression. Analysis of PD-1 expression on total and HIV-specific CD8+ T-cells from PHI subjects revealed not only an association with disease progression but also with skewed memory CD8+ T-cell differentiation. Most notably, significant direct correlations were obtained between the functional capacity of CD8+ T-cells to inhibit viral replication in vitro with higher proportions of fully-differentiated HIV-specific CD8+ TTE cells, both at baseline and at 12 months post-infection. Thus, a relationship between preservation of CD8+ T-cell differentiation pathway and cell functionality was established. This report presents evidence concerning the link among CD8+ T-cell function, phenotype and virus control, hence supporting the instauration of early interventions to prevent irreversible immune damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiretroviral Therapy, Highly Active
  • CD4 Lymphocyte Count
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Case-Control Studies
  • Cell Differentiation
  • Cytokines / blood
  • Cytokines / metabolism
  • Disease Progression
  • Epitopes, T-Lymphocyte / immunology
  • HIV / immunology*
  • HIV Infections / drug therapy
  • HIV Infections / immunology*
  • HIV Infections / metabolism
  • HIV Infections / virology*
  • Humans
  • Immunologic Memory / immunology*
  • Immunophenotyping
  • Lymphocyte Activation
  • Peptides / immunology
  • Phenotype
  • Programmed Cell Death 1 Receptor / metabolism
  • T-Cell Antigen Receptor Specificity / immunology*
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • Viral Load
  • Viremia

Substances

  • Cytokines
  • Epitopes, T-Lymphocyte
  • PDCD1 protein, human
  • Peptides
  • Programmed Cell Death 1 Receptor

Grants and funding

This research was funded by grants from the Agencia Nacional de Promoción Científica y Tecnológica, ANPCYT, Grants #2008/0549 and #2011/1658 to MMG, Grant #2011/0271 to HS and a grant from Universidad de Buenos Aires (UBACyT 2013-201620020120200263BA) to GT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.