Characterization of high avidity CD4+ T cells in HIV Controllers

Background: HIV Controllers spontaneously control HIV replication to very low levels (< 50 copies HIV RNA/mL) in the absence of antiretroviral treatment. We previously reported that HIV Controllers harbor a pool of memory CD4+ T cells with the capacity to recognize the immunodominant Gag293 peptide with a particularly high TCR avidity. Since this property may allow the persistence of an activated cellular response against minimal amounts of virus, we set to further characterize the nature of these high avidity memory CD4+ T cells. Methods: HIV Controllers from the ANRS CO18 cohort (n=8) with a viral load < 50 copies/mL for over 10 years were compared to efficiently treated patients with a similarly undetectable viral load for over 10 years (HAART group, n=8). Primary CD4+ T cell lines were generated by stimulating PBMC with decreasing doses of the Gag293 peptide. Cytokine production was monitored by IFN-γ ELISPOT and intracellular cytokine staining assays. TCR diversity was evaluated by staining with a panel of 24 anti-TCR Vβ chain antibodies and by Immunoscope analysis. Results: After stimulation with a high dose of Gag293 peptide (10-5 M), IFN-γ-positive CD4+ T cell lines were obtained for all patients studied (response rate of 8/8 in both groups). However, at low peptide doses, specific cell lines were obtained only for HIV Controllers (response rate of 6/8 at 10-9 M and 3/8 at 10-11 M) but not for treated patients. The Vβ repertoire appeared more restricted in cell lines stimulated with low peptide doses, suggesting that only a subset of HIV Controller memory CD4+ T cells were of high avidity. Conclusion: The presence of a high avidity subset within the pool of Gag293-specific memory CD4+ T cells is unique to HIV Controllers