HIV Controller CD4+ T cells preferentially express a public TCR clonotype that confers high avidity responses against Gag
Background: HIV
Controllers are rare patients who spontaneously control HIV replication to levels
below 50 copies viral RNA/ml in the absence of antiretroviral therapy. We
previously reported that HIV Controllers harbor a pool of memory CD4+ T cells
able to respond to minimal amounts of virus, due to the expression of T cell
receptors (TCRs) with high avidity for immunodominant Gag epitopes. We set to characterize
these high avidity TCRs at the molecular and functional levels.
Methods: HIV
Controllers from the ANRS CO21 CODEX cohort (n=8) were compared to efficiently
treated patients (n=8). Primary CD4+ T cell lines were generated by stimulating
PBMCs with decreasing doses of the immunodominant Gag293 peptide. Specific CD4+
T cells were labeled with Gag293-loaded MHC class II tetramers and sorted. The TCR
repertoire of tetramer+ cells was evaluated by CDR3 length polymorphism
analysis (Immunoscope) and sequencing. Highly represented TCR Vα and Vβ chains were
cloned in bicistronic lentiviral vectors and tested for CD69 induction and
cytokine production.
Results: Stimulation
with low Gag293 peptide doses generated IFNγ-positive CD4+ T cell lines for HIV
Controllers, but rarely for treated patients, confirming the predominance of
high avidity cells in the Controller group. Immunoscope analysis revealed a
major amplification of TCR Vα24 chains with a 10 a.a. CDR3 in sorted tetramer+ cells
from Controllers, while this amplification was rarely detected in treated
patients (P< 0.05). Sequencing revealed the presence of a public TCR Vα24-J17 clonotype shared by 6 Controllers and 2 treated patients. TCRs
comprised of the public Vα24 chain and of highly expressed Vβ chains
conferred high avidity Gag293 recognition and polyfunctionality to transduced T
cells. One of these TCRs could achieve Gag293 recognition in the context of 4
distinct HLA-DR molecules, possibly explaining its public nature.
Conclusions: We
identified a highly prevalent TCR sequence preferentially expressed by
Gag-specific CD4+ T cells from HIV Controllers. This public clonotype confers
high avidity polyfunctional responses to Gag, raising the possibility that it
could be used as molecular marker of efficient responses against HIV.
D. Benati1, M. Galperin1, O. Lambotte2, A. Lim3, B. Lemercier3, M. Mukhopadhyay1, M. Claireaux1, S. Hendou4, F. Boufassa4, J.-F. Delfraissy2, F. Arenzana-Seisdedos1, L.A. Chakrabarti1
1Institut Pasteur, Unité de Pathogénie Virale, Paris Cedex, France, 2Bicetre Hospital, AP-HP, Internal Medicine and Infectious Diseases, Le Kremlin-Bicetre, France, 3Institut Pasteur, Groupe Immunoscope, Paris Cedex, France, 4INSERM U 1018 - CESP, Le Kremlin-Bicetre, France