Rapid perturbation in viremia levels drives increases in functional avidity of HIV-specific CD8 T cells

PLoS Pathog. 2013;9(7):e1003423. doi: 10.1371/journal.ppat.1003423. Epub 2013 Jul 4.

Abstract

The factors determining the functional avidity and its relationship with the broad heterogeneity of antiviral T cell responses remain partially understood. We investigated HIV-specific CD8 T cell responses in 85 patients with primary HIV infection (PHI) or chronic (progressive and non-progressive) infection. The functional avidity of HIV-specific CD8 T cells was not different between patients with progressive and non-progressive chronic infection. However, it was significantly lower in PHI patients at the time of diagnosis of acute infection and after control of virus replication following one year of successful antiretroviral therapy. High-avidity HIV-specific CD8 T cells expressed lower levels of CD27 and CD28 and were enriched in cells with an exhausted phenotype, i.e. co-expressing PD-1/2B4/CD160. Of note, a significant increase in the functional avidity of HIV-specific CD8 T cells occurred in early-treated PHI patients experiencing a virus rebound after spontaneous treatment interruption. This increase in functional avidity was associated with the accumulation of PD-1/2B4/CD160 positive cells, loss of polyfunctionality and increased TCR renewal. The increased TCR renewal may provide the mechanistic basis for the generation of high-avidity HIV-specific CD8 T cells. These results provide insights on the relationships between functional avidity, viremia, T-cell exhaustion and TCR renewal of antiviral CD8 T cell responses.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Retroviral Agents / therapeutic use
  • Antibodies, Viral / analysis*
  • Antibody Affinity
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Chronic Disease
  • Cohort Studies
  • Cross-Sectional Studies
  • Cyclosporine / therapeutic use
  • Disease Progression
  • Epitope Mapping
  • HIV / drug effects
  • HIV / growth & development
  • HIV / immunology*
  • HIV / isolation & purification
  • HIV Infections / blood
  • HIV Infections / drug therapy
  • HIV Infections / immunology*
  • HIV Infections / virology
  • Humans
  • Immunity, Cellular* / drug effects
  • Immunosuppressive Agents / therapeutic use
  • Longitudinal Studies
  • Receptors, Antigen, T-Cell / biosynthesis*
  • Receptors, Antigen, T-Cell / chemistry
  • Receptors, Antigen, T-Cell / metabolism
  • Up-Regulation / drug effects
  • Viremia / blood
  • Viremia / drug therapy
  • Viremia / immunology*
  • Viremia / virology
  • Virus Replication / drug effects

Substances

  • Anti-Retroviral Agents
  • Antibodies, Viral
  • Immunosuppressive Agents
  • Receptors, Antigen, T-Cell
  • Cyclosporine

Grant support

The research leading to these results was supported by the Swiss National Science Foundation and by the Swiss Vaccine Research Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.