- Poster presentation
- Open Access
HLA-Cw*0102-restricted HIV-1 p24 epitope variants can modulate the binding of the inhibitory KIR2DL2 receptor and primary NK cell function
© Koerner et al; licensee BioMed Central Ltd. 2012
- Published: 13 September 2012
- Natural Killer Cell
- Natural Killer Cell Function
- Primary Natural Killer Cell
- Target Cell Recognition
- KIR2DL2 Receptor
Recently, it was shown that Natural Killer (NK) cell-mediated immune pressure can result in the selection of HIV-1 escape mutations contributing to accumulating evidence suggesting that NK cells play an important role in the control of HIV-1 infection. Selection of HLA class I-presented HIV-1 epitopes that allow for engagement of inhibitory killer cell Ig-like receptors (KIRs) might serve as a potential mechanism for NK cell escape. We therefore investigated the consequences of sequence variations within HLA-Cw*0102-restricted epitopes on the interaction with KIR2DL2 using a large panel of HIV-1 p24 Gag peptides.
A total of 217 decameric peptides spanning HIV-1 p24 Gag and overlapping by 9aa were screened for HLA-Cw*0102 stabilization by co-incubation with Cw*0102(+) TAP-deficient T2 cells using a flow cytometry-based assay. KIR2DL2 binding was assessed using KIR2DL2-Fc. Function of KIR2DL2(+) NK cells was flow cytometrically analyzed by measuring degranulation of primary NK cells after co-incubation with peptide-pulsed T2 cells.
We identified 11 peptides stabilizing HLA-Cw*0102 on the surface of T2 cells. However, only one peptide (p24 Gag209-218) also allowed for binding of KIR2DL2. Notably, functional analysis showed significant inhibition of KIR2DL2(+) NK cell function in the presence of p24 Gag209-218-pulsed T2 cells, while degranulation of KIR2DL2(-) NK cells was not affected. Moreover, we demonstrated that sequence variations in position 7 of this epitope observed frequently in naturally occurring HIV-1 sequences can modulate binding to KIR2DL2.
Our results show that variations in HIV-1 peptides presented by HLA can modulate target cell recognition by NK cells. Understanding the mechanisms that determine NK cell-mediated recognition of HIV-1-infected cells will be a critical step for harnessing NK cell immunity for vaccine design, in particular given the recent discovery of virus-specific memory NK cells in mice (Paust et al., Nat Imm 2009). This study was supported by the NIH, Ragon Institute and HU CFAR.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.