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

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.

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

“…Moreover, several studies in active chronic infections established links between the magnitude of T-cell stimulation (or TCR avidity) and T-cell fate. Accordingly, lower avidity or weaker stimulated T-cells are more prone to retain a normal phenotype while higher avidity T-cells acquire a chronic infection phenotype or become deleted 62,63 . This is somewhat reminiscent of the fact that T-cells retain a rather normal effector phenotype in latent infections in which T-cells most likely receive lower TCR stimulation due to a lower level of antigen-exposure.…”

High-throughput monitoring of human tumor-specific T-cell responses with large peptide pools

“…In contrast to CD8 C T cells, CD4 C T cells recognize epitopes presented by MHC class II molecules and libraries of longer (20-mer) overlapping peptides are generally used to screen for antigen-specific responses. 19 We thus measured the response of Melan-A/ MART-1 [25][26][27][28][29][30][31][32][33][34][35][36] -specific CD4 C T-cell clones 20 spiked into PBMCs of HLA-DQ6 C donors in the presence of 20-mers overlapping peptide pools (1 mM each). As shown in Fig.…”

“…CD4 C blasts were used after at least 10 d of culture. For long-term in vitro stimulation, PBMCs from 5 HLA-A2C donors were stimulated in 24 well-plates (4 £ 10 6 cells/ well) for one week with 0.1 mM Melan-A [26][27][28][29][30][31][32][33][34][35] (A27L) in the presence or absence of MAGE-A3 peptide pool (0.1 mM each peptide). After 48 h of incubation at 37 C, 100 U/mL IL-2 were added to the culture.…”

“…EC50 was determined as the peptide concentration needed to achieve a half-maximal response as previously described. 27 Intracellular cytokine staining / Flow cytometry IFNg and TNF-a cytokine secretion was investigated by ICS. The following monoclonal antibodies were used at predetermined optimal concentrations: anti-CD3¡PerCP-Cy5.5 (eBioscience), anti-CD8 C ¡AF488, anti-CD4¡PE-Cy7, antiIFNg¡BV421, anti-TNFa¡AF647 (Biolegend).…”

“…The background obtained with corresponding irrelevant peptide pools alone or non-stimulated cells were subtracted from values obtained in the presence of cognate peptide C irrelevant peptide pool or specific peptide alone, respectively. The proliferation of Melan-A 26-35 -specific CD8 C T cells was assessed by tetramer staining using PE-labeled Melan-A [26][27][28][29][30][31][32][33][34][35] tetramer (TcMetrix), FITC conjugated CD8 C and aqua live/ dead stain kit.…”