Research Article: Rapid Perturbation in Viremia Levels Drives Increases in Functional Avidity of HIV-specific CD8 T Cells

Date Published: July 4, 2013

Publisher: Public Library of Science

Author(s): Selena Viganò, Felicitas Bellutti Enders, Isabelle Miconnet, Cristina Cellerai, Anne-Laure Savoye, Virginie Rozot, Matthieu Perreau, Mohamed Faouzi, Khalid Ohmiti, Matthias Cavassini, Pierre-Alexandre Bart, Giuseppe Pantaleo, Alexandre Harari, Guido Silvestri.


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.

Partial Text

CD8 T cells play a critical role in antiviral immunity and a large number of studies in both human and murine models indicate that virus-specific CD8 T cells are directly involved in the control of virus replication and disease progression [1], [2], [3], [4], [5], [6], [7].

T-cell functional avidity reflects the ability of T cells to respond to various concentrations of Ag and may be assessed ex vivo through a quantification of a biological function such as IFN-γ production, cytotoxic activity or proliferation capacity. Several parameters concur to determine the threshold of T-cell responsiveness. These include: a) the affinity of the TCR for the peptide-MHC (pMHC) molecule, i.e. the strength of the interaction between the TCR and pMHC [41], [42], b) the density of pMHC-TCR interactions (reflecting both the amount of Ag and the ability of Ag presenting cells (APC) to present Ags) [43], [44], [45], [46], c) the expression of co-stimulatory and co-inhibitory molecules by T cells and APC [47], and d) the T-cell distribution and composition of signaling molecules [44], [48]. However, the factors determining functional avidity and the relationship between functional avidity and the heterogeneity of T-cell responses are not well understood.




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