An early HIV mutation within an HLA-B*57-restricted T cell epitope abrogates binding to the killer inhibitory receptor 3DL1
Brackenridge S, Evans EJ, Toebes M, Goonetilleke N, Liu MK, di Gleria K, Schumacher TN, Davis SJ, McMichael AJ, Gillespie GM. (2011), J Virol. 85, 5415-22
Mutations within MHC class I-restricted epitopes have been studied in relation to T cell-mediated immune escape, but their impact on NK cells via interaction with killer Ig-like receptors (KIRs) during early HIV infection is poorly understood. In two patients acutely infected with HIV-1, we observed the appearance of a mutation within the B*57-restricted TW10 epitope (G9E) that did not facilitate strong escape from T cell recognition. The NK cell receptor KIR3DL1, carried by these patients, is known to recognize HLA-B*5703 and is associated with good control of HIV-1. Therefore, we tested whether the G9E mutation influenced the binding of HLA-B*5703 to soluble KIR3DL1 protein by surface plasmon resonance, and while the wild-type sequence and a second (T3N) variant were recognized, the G9E variant abrogated KIR3DL1 binding. We extended the study to determine the peptide sensitivity of KIR3DL1 interaction with epitopes carrying mutations near the C termini of TW10 and a second HLA-B*57-restricted epitope, IW9. Several amino acid changes interfered with KIR3DL1 binding, the most extreme of which included the G9E mutation commonly selected by HLA-B*57. Our results imply that during HIV-1 infection, some early-emerging variants could affect KIR-HLA interaction, with possible implications for immune recognition.
Key figure: Integrity and specificity of soluble KIR3DL1-Fc
(A) The integrity of KIR3DL1-Fc was assessed by antibody binding, using the KIR3DL1-specific antibodies Z27 (which binds a linear epitope) and DX9 (conformation dependent). After the level of saturation binding of each antibody was corrected for the amount of KIR3DL1 protein immobilized in the SPR flow cell, the proportion of DX9-reactive material (correctly folded) to Z27-reactive material (total protein) was calculated as 61%. (B) The specificity of KIR3DL1 was assessed by comparing its binding to immobilized HLA-B*5703 (Bw4 motif) and B*8101 (Bw6 motif) complexes. (C) The preferential binding of KIR3DL1 to Bw4 serotypes does not reflect differences in the amounts of protein immobilized in the SPR flow cell. The data were corrected for the amount of MHC class I protein immobilized in each flow cell and are shown as both normalized binding (with the level of binding to HLA-B5703 set at 1) and fold change in binding of HLA-B*8101 compared with HLA-B*5703.